Normal Tension Glaucoma: Are We Missing It?

In clinical practice, we frequently encounter patients who present with almost all of the diagnostic findings of primary open-angle glaucoma (POAG) – but whose intraocular pressure (IOP) is in the normal range. It is a challenging clinical scenario because, for decades, we believed elevated IOP was the defining diagnostic feature of glaucoma. Today, it’s recognized that elevated IOP is not integral to a diagnosis of glaucoma when optic nerve damage is observed in the absence of other explanations for disc abnormality and/or visual field loss (1). Yet, the myth that elevated IOP must be present for a diagnosis of glaucoma persists, which means that many clinicians frequently fail to detect normal tension glaucoma (NTG) until it reaches an advanced stage. If a clinician fails to suspect NTG in patients whose IOP lies within the normal range (12–22 mmHg), they may decide not to perform a careful optic nerve exam, and thereby miss the early signs of glaucomatous optic neuropathy (2).

Without high IOP, NTG is harder to detect and more challenging to manage than high tension POAG (HT-POAG) in several important ways. In a large epidemiologic study assessing the prevalence of glaucoma, it was found that an estimated 30 percent of patients diagnosed with OAG had NTG (3)(4), and Asian populations appear to be particularly prone to NTG; the Japanese Tajimi study cited a POAG prevalence of 3.9 percent, of which 92 percent had NTG (3)(5). In this article, I will examine the differences between NTG and HT-POAG and outline strategies for optimal detection and management.

NTG: Does it exist?

The first question to consider is: does NTG exist as a distinct disease entity? It is worth noting that the term NTG was coined to describe patients who had all of the typical optic nerve and visual field findings of POAG except for elevated IOP. Thus, it is not surprising that NTG and HT-POAG share many of the same risk factors. Granted, some are more common in NTG, such as migraine and poor circulation/vascular dysregulation, than in POAG (Box 1: Risk Factors for Glaucoma). Likewise, some clinical findings, such as disc hemorrhage, acquired pits of the optic nerve, and certain patterns of disc cupping and visual field loss, may be more common in NTG than in HT-POAG. But none is pathognomonic for either entity, so rather than thinking of them as separate diseases, it might be more productive to consider NTG to be a subset of POAG, and to acknowledge that POAG exists across the entire spectrum of IOP (3).

Clearly, though elevated IOP is a risk factor for glaucoma, it is neither necessary nor sufficient to explain the presence of glaucoma. For people who develop OAG and yet have IOP in the normal range, other as-yet unidentified pathophysiologic processes must be at play, such as vascular dysregulation.

Approach to treatment

My next comment may sound obvious, but the first step in preventing visual dysfunction caused by NTG is to screen for it. I recommend that every patient receives a careful screening evaluation of the optic nerve, the nerve fiber layer, and the peripapillary region, regardless of his or her IOP (Box 2: Screening for NTG in the Clinic).

Evidence from major clinical trials, including the Early Manifest Glaucoma Trial, the Advanced Glaucoma Intervention Study, and the Collaborative Normal-Tension Glaucoma Study (CNTGS), have confirmed that medical and surgical interventions geared toward lowering IOP can delay or prevent the progression of glaucoma, including NTG (6)(7)(8).

The CNTGS, which randomized patients with NTG to receive treatment or no treatment, showed that patients in the treatment arm (medications, laser or surgery) fared much better than those randomized to the no-treatment arm, achieving a nearly threefold reduction in progression over five years (35 percent in the treatment arm versus 12 percent in the no-treatment arm) (8). However, among untreated patients with normal IOP but abnormal looking optic nerves, two-thirds (65 percent) did not progress during five or more years of follow up (8).

When we see typical glaucomatous optic nerve and visual field changes in an eye with elevated IOP, it is logical and usually correct to attribute the damage to the IOP and thus to POAG. In eyes with optic nerve and visual field damage but normal IOP, we must first rule out non-glaucomatous causes of nerve damage (Box 3: Differential Diagnosis of NTG). In addition to the entities in Box 3, we should also consider the possibility that our patient may simply have odd-looking but otherwise healthy optic nerves, or may have had prior optic nerve insults that are now historical and non-progressive – for instance, a remote history of systemic steroid use with damage that occurred years or decades in the past and is now static.

In light of these considerations (including the numbers of NTG patients in the CNTGS that did not progress), once I’ve diagnosed a patient with NTG, the initial clinical challenge becomes deciding whether treatment is indicated. A compelling case can be made for deferring or delaying treatment in a “watchful waiting” approach to many patients with NTG. Those who don’t progress over a several-year period of observation, or who progress very little in such a time frame, may be at low risk for developing visual dysfunction from glaucoma in their remaining lifetimes.

So, who should receive treatment – and when? What are the clinical criteria for initiating treatment in patients with glaucoma and normal IOP? Immediate treatment is generally indicated for patients who present with the following:

• Sight-threatening visual field loss at initial diagnosis 
• A clear history of visual field loss and/or progression of optic nerve damage at their current pressure 
• Blindness in one eye, regardless of the disease stage in the other eye 
• A strong family history of vision loss related to glaucoma.

Clinical management strategies in NTG 

The CNTGS defined the gold standard for treatment (whether medical or surgical) as a 30 percent reduction in IOP from baseline (8). In other words, my treatment target for a patient with glaucoma at an IOP level of 16 mmHg might be 11 mmHg. Fortunately, advances in topical drug therapy and/or selective laser trabeculoplasty (SLT) enable us to achieve this goal in the majority of patients with NTG without having to resort to incisional surgery.

Currently, five classes of IOP-lowering agents, which work by mechanisms affecting aqueous production and outflow, are available. These include: prostaglandin analogs (PGAs), beta-blockers, carbonic anhydrase inhibitors (CAIs), adrenergic agonists, and miotics (9).

Despite the advantages of PGAs and availability of multiple drug options, there is information that suggests that a significant proportion of glaucoma patients do not reach target IOP with a single-agent regimen (10). In addition, even if IOP is maintained within target levels, some patients may continue to develop progressive glaucoma damage and field loss (6). These treatment challenges highlight a continued need for additional therapies. A number of glaucoma patients, including some with NTG, require greater IOP reduction than others. Effective IOP reduction may require pressures close to 10 mmHg or even lower around the clock, and it may be difficult to reduce pressures to such levels with either a single agent or multiple agents. Even with multiple medications – which can adversely impact adherence (11) – pressures in this range can be difficult to attain in most patients. 

My standard approach to treating glaucoma is to start with either a PGA or SLT, whichever the patient prefers. Subsequently, if first-line therapy fails, I will step up to second-line therapy with whichever intervention the patient did not choose initially. Third-line options involve a combination approach in which either a CAI, a β-blocker, or an α2 adrenergic agonist is added to a PGA. Of these three agents, numerous studies support the addition of the CAI to a PGA regimen to produce the most robust IOP reduction (12)(13)(14). However, when aiming to achieve aggressive IOP reduction, I might also choose to maximize adjunctive therapy by going straight to a fixed-dose combination product added to PGA therapy. The bottom line: we can now add any combination of these three adjunctive therapies to a PGA in a fixed-dose combination.

In the event that pharmacologic therapy and SLT fail to control the patient’s NTG, incisional surgery is another option (9).

NTG take home

The treatment goal for glaucoma across the spectrum of IOP, including NTG, is to achieve an impactful IOP reduction by whatever means necessary (whether pharmacologic, SLT, or incisional surgery) to halt or delay further optic nerve damage. We have studies to support specific IOP reductions by stage of disease – for instance, a 22.5 percent reduction in ocular hypertension (15), an approximate 25 percent IOP reduction in early POAG (7), and a 30 percent reduction in NTG (8).

I use these studies as guidelines rather than absolutes. In fact, the American Academy of Ophthalmology has created evidence-based guidelines for initial POAG treatment (16). In these guidelines, an initial 25 percent IOP reduction is recommended for all forms of POAG, including NTG, with the caveat that individual risk profiles may support a more or less aggressive approach on a patient-by-patient basis.

Today the prognosis for patients with POAG across the spectrum of IOP is better than ever. Our therapeutic options continue to expand, but there is also a continued need for additional pharmacologic therapies for those patients who do not achieve their target IOP.

Our challenge as eyecare professionals is to recognize the disease in its early stages by performing a thorough ophthalmic exam on every patient who walks through the door, regardless of his or her IOP. Only with early detection can our patients with NTG benefit from the full spectrum of management options.

Tony Realini is professor of ophthalmology at the West Virginia University Eye Institute, USA. He reports that he is a consultant for Alcon, Inotek, and Bausch + Lomb and has received research support from Alcon in the last 12 months.