The term “normal-tension glaucoma” (NTG) is a trap, an oxymoron, and a frustrating nuisance to patient and physician alike. The uncertainty clinicians feel about NTG is captured in the name — with 3 words, we express our perplexity about a condition that is supposed to be caused by high intraocular pressure (IOP), except it isn’t. This article aims to demystify at least some aspects of this condition (or collection of conditions) that have been thrown into this diagnostic waste basket.

Ophthalmologists reading this article may notice disdain in my writing, and many will lament with me, about a diagnosis that puts our backs against a wall and gives us an uncomfortable sense of ambiguity when we use it. Let’s try to untangle this problem as best we can with current evidence.

Characteristics of Normal-tension Glaucoma

Unlike the patient population that was defined by the landmark Ocular Hypertension Treatment Study (OHTS) trial, patients with NTG have statistically normal intraocular pressures.^1-3 The OHTS trial showed that reducing elevated IOPs decreases the risk of glaucoma progression.¹ This approach becomes more complicated in cases of normal-tension glaucoma, because these patients’ in-office IOPs are already normal. The rationale for further lowering a statistically normal IOP is that eyes with asymmetric glaucomatous damage had higher (albeit still normal) IOPs in the worse eye.² These and many other insights were uncovered by the Collaborative Normal-Tension Glaucoma Study Group (CNTGS) and their landmark trials in normal-tension glaucoma. For those interested in a deeper understanding of the background of NTG, the CNTGS trials are an excellent place to start, and I will draw heavily from their papers as well as from the work of Drance et al.

Other factors contribute to the progression of glaucoma besides IOP.⁴ In normal-tension glaucoma, it becomes even more important to investigate these factors. We do have some leads when it comes to non-IOP risk factors. Drance hemorrhages — hemorrhages that run with the nerve fibers in the optic disc — have been shown to be a highly significant harbinger of progression.⁴ Circulatory disorders have also been implicated: hemodynamic crises, nocturnal hypotension, systemic hypotension, and too-rapid correction of systemic hypertension.^5-7 Patients who are migraine sufferers were also more likely to progress in the same study. The mechanism here seems to be vasospasm, and it seems reasonable to ask about migraine or Raynaud syndrome symptoms — this will at least be helpful in determining which patients need more frequent follow-up because of increased risk of progression.^5,8,9

Multiple studies have found links between sleep apnea and NTG.^10,11 Two conditions that I routinely investigate for NTG patients are undiagnosed and untreated sleep apnea with a sleep study, and nocturnal hypotension with 24-hour blood pressure monitoring. The common thread between all of these is perfusion of the optic nerve, so any interventions that can help with perfusion can help prevent progression. I usually tell my glaucoma patients that “anything that is good for your circulation is good for your optic nerve.” Sometimes, though, the best treatment is still to chase an even lower IOP.

Surgical Considerations

Interventions that lower IOP from an already low baseline are riskier filtering surgeries, in which the goal is to get closer to the episcleral venous pressure. Complications of filtering surgery can be devastating (chronic hypotony, choroidal hemorrhages, and bleb leaks, to name a few). Accelerated cataract formation can diminish the benefit of filtering surgery for these patients,³ and subsequent cataract surgery can cause the original filtering surgery to fail. As such, the risks and benefits of filtering surgery should be carefully weighed with the patient.

It’s also wise to consider a patient’s age and frailty when choosing whether to do filtering surgery and when choosing which procedure to perform. This should always be an individualized decision. A 5-year prospective trial in Japanese patients with NTG whose mean baseline IOP was 12.3 mmHg without treatment, found that mean deviation (MD) decreased by -0.33 dB/year. The probability of progression was 66%.¹² For some patients, especially younger patients, this may be unacceptable. For others, the difficulties of going through filtering surgery, even if routine and successful, may be too much.

I would even suggest taking care, as a referring ophthalmologist, to explore some of these pros and cons before referring to a glaucoma subspecialist. Giving some indication of the patient’s preferences to the subspecialist can be very helpful because the referring provider often has the advantage of knowing the patient for some time. Are they likely to be compliant with postoperative care? Would they prefer to have filtering surgery, or do they just want to be monitored, accepting the higher risk of progression? If you are the subspecialist, contact the referring provider and ask them some of these questions if you are uncertain how to proceed.

Once other risk factors have been identified and treated, one can be left with the daunting prospect of lowering the patient’s IOP to levels flirting with hypotony or watching them progress and continue to lose visual field despite having pressures that look very reasonable in the office. Thankfully, newer developments in the management of glaucoma can offer some relief for both the ophthalmologist and the patient. One of these developments occurred with the introduction of home tonometry. Icare has a product called the Icare Home2, which enables patients to take IOP readings outside of the office. There is excellent agreement between these new self-tonometers and Goldmann applanation tonometry,¹³ opening a whole new sphere of convenient at-home IOP monitoring.

Monitoring IOP at Home

Providing home monitoring can often affect management decisions for these patients.¹⁴ In my own experience, I have seen nocturnal IOP spikes uncovered by home monitoring that would occur in patients who would otherwise only have their pressures monitored during office hours. Discovering these higher nocturnal pressures in some patients with an NTG diagnosis suggests that these patients might actually be experiencing a more normal sort of glaucoma than previously thought — they do have high IOPs, but it is not recorded during office visits. Patients with previously unmeasured IOP spikes might therefore benefit from filtering surgery even when their in-office pressures remain normal, assuming the surgical procedure can dampen the nocturnal IOP spikes. Postoperative home monitoring with a self-tonometer would then continue to be useful, to determine whether the procedure successfully eliminated those nocturnal IOP spikes.

Furthermore, the IOP target might not need to be as aggressively low if we know, for example, that a certain NTG patient had nocturnal spikes into the 20s. Pair this with the new paradigm of MIGS surgery and we might be able to treat a certain subset of NTG patients who have occult IOP spikes with less risky surgeries.

When considering home IOP monitoring, it would be ideal for the patient to use the self-tonometer for about a week. Patients should be encouraged to take as many measurements as possible during that time. Patients should also aim to wake up on a few occasions during the week and measure their IOP during periods when they would usually be sleeping.

One feature of the Icare Home2 device is that patients cannot see their IOP readings when they take them; they must be uploaded to a computer in the clinic. This keeps patients from becoming overly anxious about any IOP spikes during the testing period (remember, these patients are used to having consistently normal IOPs). I schedule a visit specifically to go over their home-monitoring results in the office, and I do not share their test results with them before that visit.

Conclusion

Although self-tonometry, uncovering nocturnal IOP spikes, and less-risky MIGS surgeries can offer some reprieve for us and our patients, there still exists the true NTG patient whose disease continues to progress even though every modifiable risk factor has been addressed and his or her IOPs are consistently normal at all times. In such cases, the evidence we currently have indicates that lowering IOP further will help slow progression.³

It will be interesting to see how the story of NTG unfolds as we gain more understanding and newer monitoring capabilities. One can barely write an article these days without mentioning artificial intelligence (AI), but the alluring possibilities that AI offers for making sense of such multifaceted problems like NTG are exciting. It is already showing promise in the diagnosis of glaucoma and prediction of the disease’s progression.^15,16 Perhaps one day, AI-driven algorithms will serve as a ubiquitous tool for the management of NTG.

In summary, look for disc hemorrhages, explore non-IOP risk factors, order a sleep study and 24-hour BP monitoring, consider home tonometry, and decide on a treatment strategy with the patient’s preferences in mind if further IOP lowering is required. Normal-tension glaucoma is a challenging condition and patients must be included in the decision-making process. Be honest with them about the limits of our understanding when it comes to NTG, and about the greater risks associated with very-low IOPs. Such inclusion can be very rewarding, and I have found that patients are very appreciative of the highly individualized care that we provide.

Matthew Brink, MD, specializes in glaucoma and advanced anterior-segment surgery at the Center for Excellence in Eye Care in Miami, Florida. He reports no relevant disclosures. Reach him at mbrinkmd@gmail.com.

References

1. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714-830. doi:10.1001/archopht.120.6.714
2. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126(4):487-497. doi:10.1016/s0002-9394(98)00223-2. Erratum in: Am J Ophthalmol. 1999;127(1):120.
3. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126(4):498-505. doi:10.1016/s0002-9394(98)00272-4
4. Drance SM, Sweeney VP, Morgan RW, Feldman F. Studies of factors involved in the production of low-tension glaucoma. Arch Ophthalmol. 1973;89(6):457-465. doi:10.1001/archopht.1973.01000040459003
5. Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131(6):699-708. doi:10.1016/s0002-9394(01)00964-3
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9. Hayreh SS, Zimmermann MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117(5):603-624. doi:10.1016/s0002-9394(14)70067-4
10. Sergi M, Salerno DE, Rizzi M, et al. Prevalence of normal tension glaucoma in obstructive sleep apnea syndrome patients. J Glaucoma. 2007;16(1):42-46. doi:10.1097/01.ijg.0000243472.51461.24
11. Mojon DS, Hess CW, Goldblum D, et al. Normal-tension glaucoma is associated with sleep apnea syndrome. Ophthalmologica. 2002;216(3):180-184. doi:10.1159/000059625
12. Sakata R, Yoshitomi T, Iwase A, et al. Factors associated with progression of Japanese open-angle glaucoma with lower normal intraocular pressure. Ophthalmology. 2019;126(8):1107-1116. doi:10.1016/j.ophtha.2018.12.029
13. Perez-Garcia P, Morales-Fernandez L, Saenz-Frances F, et al. Comparison of intraocular pressure measured using the new icare 200 rebound tonometer and the Perkins applanation tonometer in healthy subjects and in patients with primary congenital glaucoma. Arch Soc Esp Oftalmol (Engl Ed). 2021;96(4):175-180. doi:10.1016/j.oftal.2020.06.007
14. Sood V, Ramanathan US. Self-monitoring of intraocular pressure outside of normal office hours using rebound tonometry: initial clinical experience in patients with normal tension glaucoma. J Glaucoma. 2016;25(10):807-811. doi:10.1097/IJG.0000000000000424
15. Medeiros FA, Jammal AA, Thompson AC. From machine to machine: an OCT-trained deep learning algorithm for objective quantification of glaucomatous damage in fundus photographs. Ophthalmology. 2019;126(4):513-521. doi:10.1016/j.ophtha.2018.12.033
16. Nitta K, Tachibana G, Wajima R, et al. Predicting lifetime transition risk of severe visual field defects using Monte Carlo simulation in Japanese patients with primary open-angle glaucoma. Clin Ophthalmol. 2020;14:1967-1978. doi:10.2147/OPTH.S247618