August 28, 2025
5 min read
Key takeaways:
- IOP lowering is effective for the treatment of normal-tension glaucoma.
- Normal-tension glaucoma is easy to miss, so pay closer attention to optic nerve and OCT imaging during certain eye exams.
Normal-tension glaucoma is typically defined as open-angle glaucoma with IOP that is 21 mm Hg or less. Despite the seemingly “normal” IOP, there is progressive damage to the optic nerve.
In many Asian countries, normal-tension glaucoma (NTG) is the dominant form of glaucoma, accounting for 70% of all POAG cases in China (Zhao et al.), 77% in Korea (Kim et al.) and 92% in Japan (Iwase et al.). But even among white, Black and Hispanic populations in the U.S., NTG is not uncommon, accounting for approximately 25% to 50% of all open-angle glaucoma (OAG) cases. Myopes are more likely to develop NTG, and we often see it in patients presenting with glaucoma at younger ages who typically are thin and have low blood pressure and/or migraines.
Like most OAG cases, NTG often begins with the classical visual field loss patterns of a nasal step or arcuate scotoma, but a significant percentage of NTG patients have visual field loss in the central 10° (Caprioli et al.). This can arise in the early stages of NTG, and, as a consequence, patients experience a greater impact on activities of daily living.
NTG presents quite a management conundrum because our treatments for glaucoma — whether medical, laser or surgical — all are approved to lower IOP, which is more difficult to achieve when the pressure is already low at baseline. It is much easier to reduce a starting pressure of 30 mm Hg to 21 mm Hg than to get the same 30% reduction in a patient with a baseline IOP of 15 mm Hg.
Two decades ago, the Collaborative Normal Tension Glaucoma Study (CNTGS) answered the question about whether IOP reduction could help slow NTG progression. CNTGS showed that there was a slower rate of visual field loss when IOP was reduced by a target of 30% or more, which has guided treatment since (Anderson et al.). Today, most practitioners will start treatment of NTG with a topical prostaglandin analog, the medication class with the best chance of achieving that initial 30% or greater pressure lowering. When it comes to surgical options, more invasive procedures like trabeculectomy tend to be favored for NTG over minimally invasive glaucoma surgery (MIGS), for the same reason.
New approaches
It is likely that IOP-independent factors are an important component of managing NTG. We know from the Low-Pressure Glaucoma Study that patients treated with brimonidine were less likely to progress than those on timolol, even though the mean IOP lowering was similar in both groups (Krupin et al.).
More recently, evidence has been emerging that episcleral venous pressure (EVP) may play a role in NTG. Typically, glaucoma therapy is aimed at either “turning down the faucet” by decreasing aqueous production or “unplugging the drain” by increasing outflow through the trabecular meshwork (TM). However, normal outflow may also be constrained by back pressure from the episcleral veins and collector channel systems. Indeed, the distal venous outflow system may counteract the effect of TM bypass, limiting the clinical efficacy of many MIGS procedures (Strohmaier et al.).
The episcleral veins are distal to the TM and, according to Goldmann’s equation, provide back pressure and/or resistance that adds to and can even elevate IOP. It stands to reason, therefore, that decreasing EVP could lower the floor for IOP, making the eye more responsive to IOP-lowering medications and procedures. This could be helpful across the board, but particularly in NTG, where we suspect that EVP plays an outsized role (Selbach et al.).
Rho kinase (ROCK) inhibitors such as netarsudil and ripasudil primarily affect the proximal outflow system at the TM, but they have a secondary effect on EVP (Sit et al.). So far, we have no available medications that selectively target tissues distal to the TM to more directly reduce distal outflow resistance and EVP. However, an investigational drug currently in clinical studies (QLS-111, Qlaris Bio) holds promise. Preclinical work with this class of drugs (ATP-sensitive potassium channel openers) suggests that they can modulate distal outflow, and QLS-111 could be the first medication to primarily lower IOP through EVP reduction.
In two recently completed phase 2 studies, QLS-111 met all of its primary and secondary endpoints. In the first study, called Osprey, the data demonstrated that the 0.015% concentration, used once daily in the evening, was the most efficacious dose and regimen, resulting in mean IOP lowering of 3.7 mm Hg from baseline (Wirostko et al.).
In the second study, called Apteryx, QLS-111 0.015% also demonstrated an additive IOP reduction of 3.2 mm Hg to 3.6 mm Hg in patients who were already on latanoprost, from a baseline of 19.8 mm Hg, suggesting robust additivity to current prostaglandin therapies. Importantly, QLS-111 had an excellent safety and tolerability profile, with no clinically relevant adverse events. There was no significant hyperemia when dosed alone and no incremental hyperemia when added to latanoprost for over 28 days. Not only is this an advantage for any topical therapy for a chronic disease, but it is particularly advantageous in a drug with a unique mechanism of action, given that we have seen drug-related adverse events associated with both brimonidine and netarsudil.
The company just launched a pilot study of QLS-111 in NTG patients in South Korea, the results of which may provide important lessons about how this class of medication functions in NTG (NCT06030193).
More to learn
We still have much to learn about NTG. The prevailing theory is that in some eyes the optic nerve is highly sensitive to IOP-related damage, even at lower pressures. It may be the case that these eyes are very sensitive to alterations in blood flow and that ischemia is occurring, resulting in reduced oxygenation of the optic nerve.
There are a number of other theories about why some people with normal pressure get glaucoma. For example, patients with Flammer syndrome tend to have NTG and systemic vascular dysregulation, perhaps providing clues to the relationships between low BMI, low blood pressure, impaired perfusion and optic nerve oxygenation. Most likely, NTG is multifactorial, with some genetic component as well.
We also need better ways of diagnosing NTG. In the primary care setting, elevated IOP is easily detected and prompts a more detailed evaluation of the optic nerve and visual fields. But when IOP is in the normal range, early-stage glaucoma damage may be missed. Because of this, we often see NTG patients being diagnosed later in the course of the disease, when visual field loss is already advanced, and requiring more aggressive treatment.
More careful attention to the optic nerve and OCT imaging during routine eye exams, especially in patients over age 60 year, those in the demographic groups more likely to be affected by NTG (people of Asian descent, those with low blood pressure, Raynaud’s syndrome and/or migraines, or patients taking a systemic beta blocker) is recommended. In our experience, anyone treating a significant volume of glaucoma patients who does not have at least one-third of their patients diagnosed as NTG is likely missing many cases of NTG.
A better understanding of NTG and better strategies for slowing glaucomatous damage in patients with low IOP remains a large unmet need in glaucoma care. We are optimistic that ongoing research may get us closer to the answers for these underserved patients.
References:
- Anderson DR. Curr Opin Ophthalmol. 2003;doi:10.1097/00055735-200304000-00006.
- Caprioli J, et al. Am J Ophthalmol. 1984;doi:10.1016/0002-9394(84)90505-1.
- Iwase A, et al. Ophthalmology. 2004;doi:10.1016/j.ophtha.2004.03.029.
- Kim C, et al. Ophthalmology. 2011;doi:10.1016/j.ophtha.2010.10.016.
- Krupin T, et al. Am J Ophthalmol. 2011;doi:10.1016/j.ajo.2010.09.026.
- Selbach JM, et al. Ophthalmologica. 2005;doi:10.1159/000088378.
- Sit AJ, et al. Surv Ophthalmol. 2025;doi:j.survophthal.2025.03.003.
- Strohmaier CA, et al. Ophthalmol Glaucoma. 2025;doi:10.1016/j.ogla.2024.11.006.
- Wirostko B. QLS-111 significantly lowers IOP in phase 2 studies, Osprey and Apteryx, as monotherapy and adjunctive therapy with excellent safety and tolerability. Presented at: World Glaucoma Congress 2025; June 25-28, 2025; Honolulu.
- Zhao J, et al. Am J Ophthalmol. 2019;doi:10.1016/j.ajo.2018.10.017.
For more information:
Michael Chaglasian, OD, is associate professor and chief of innovative technology and data science at the Illinois College of Optometry in Chicago. He can be reached at mchaglas@ico.edu.
Shan Lin, MD, is research co-director at the Glaucoma Center of San Francisco. He can be reached at sl@glaucomasf.com.
Sources/Disclosures
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Disclosures:
Chaglasian reports consulting for Alcon, Bausch + Lomb and Topcon Healthcare. Lin reports being on a scientific advisory board for Qlaris Bio and being a speaker/consultant for Santen.
