Is there a typical phenotype in normal-tension glaucoma?

Luís Abegão Pinto, MD, PhD

Central Lisbon Hospital North. Visual Sciences Study Center, Faculty of Medicine, University of Lisbon, Portugal.

Primary open-angle glaucoma (POAG) is one of the main causes of blindness world-wide1. One of the main risk factors – intraocular pressure (IOP) – has been serving as a differentiating factor between two glaucoma populations: those with higher than normal values for a normal population (>21 mmHg) and those in which IOP has never reached a recorded level above 21 mmHg. The latter are identified as having normal-tension glaucoma (NTG). 

Such division is necessarily arbitrary in that normal values may vary according to the population. For example, in some Asian populations average IOP values are lower than the usual standard value of 16 mmHg. 2,3 Furthermore, patient categorization as POAG or NTG is limited to the IOP assessment hours. Considering that the IOP varies significantly during the day4, it is possible that some patients categorized as POAG have a tension peak above the 21 mmHg threshold out of the ophthalmologist's usual working hours.

Bearing in mind the classification arbitrariness, a number of authors have suggested that NTG patients have other differentiating characteristics5. Regardless of whether such clinical variables reflect a different pathophysiological mechanism in these patients, data from several studies allows us to identify some phenotypes within the NTG population, which can help clinicians not only in their classification, but also, apparently, in predicting the probable response to therapy or disease progression rate.

Although not exclusively so, GNT patients are most frequently females with a history of migraine and peripheral vasospasm. Patients with a history of peripheral vasospasm (characterized by Flammer6,7 – Table 1) more often have type A personality, are thin, are more sensitive to cold, less sensitive to thirst and even less sensitive  to antidepressive therapy. These symptoms fade with age, particularly in (postmenopausal) females.

Table 1. Typical clinical characteristics of vasospastic patients

Female gender

Low blood pressure

Type A personality

Raynaud´s phenomenon


Low body weight


The presence of underlying cardiovascular disease is relatively consensual and these patients have blood pressure values outside the normal range (either marked hypotension during night-time, diastolic blood pressure at rest lower than 90 mmHg or, oppositely, heavily medicated hypertension episodes and a history of cardiac disorders and vascular brain diseases)6,8,9.

These clinical differences can also extend to the ophthalmological examination (table 2). Several authors have suggested that there are morphological differences of the eye globe between POAG and NTG patients. The latter tend to have lower central corneal thickness, which could further influence the variable that establishes the criterion (IOP)10-12. At the ocular fundus, NTG patients seem more likely to have focal ischemic injuries at the neuroretinal rim. Nasalization of central retinal vessels is less frequent in these cases5. Furthermore, there is an increased prevalence of optic disk hemorrhages13,14. Interestingly, more recent data suggests disc morphology in NTG patients (either as assessed from structural examination or physician’s fundoscopy description) to show poorer correlation with the visual field than in POAG patients. Indeed, for patients with a similar level of visual field damage, vertical disc ratio may be larger than expected15.    

Table 2. Ophthalmological examination5,14

Central corneal thickness

Potentially lower

Optic disk

Focal ischemia at the neuroretinal rim

Increased frequency of optic disc bleeding

Emergence of non-nasalized central retinal vessels

Potencial larger cup-disc-ratio for the same level of damage than POAG patients

Publications from the Collaborative Normal-Tension Glaucoma Study13,16,17 suggest that, in clinical terms, untreated patients with a higher risk of disease progression are: Caucasians (as opposed to Asians), females, patients with a history of migraine and presence of optic disk bleeding (table 3). On the other hand, the factors that decrease likelihood of IOP reduction being able to prevent disease progression are: male gender, history of cardiovascular disease, family history of vascular brain disease and presence of optic disk bleeding.

Table 3. Characteristics associated with progression17-20

Older age

Female gender

Evidence of vasospasticity

Hypertensive drug therapy


Low body mass index


Optic disk bleeding


Characterization is particularly important in the initial approach with these patients. If we consider that the natural history of the disease suggests that a large number of NTG patients will not show evidence of progression in the long run, even when they remain untreated120, it is therefore necessary to identify which patients have more risk factors for such progression to occur. From a practical point of view, this will help the clinician for example to adjust the target IOP to lower values in these patients or to schedule their follow-up at shorter intervals for earlier identification of any signs of progression.

The blood pressure profile of these patients needs special attention. Although they often report blood pressure levels within the normal to low range, we should consider whether these patients (who generally show marked evidences of autonomic nervous system dysfunction) have marked ocular perfusion pressure drops (big dippers). Systemic blood hypotensive therapies should be investigated in these patients, and measures to avoid/deteriorate pathophysiological mechanisms associated with vascular dysfunction in these patients should be adopted (see chapter – "How can the vascular component cause glaucoma?”).  

4th Edition – May 2017