Glaucomatous optic neuropathy, also known as glaucoma, is the leading cause of irreversible blindness worldwide and the second-leading cause of overall blindness following cataracts.^1-3 There are multiple risk factors associated with glaucoma, including myopia, reduced central corneal thickness (CCT), increasing age, and family history, but none of these risk factors are modifiable.^1,4,5 Intraocular pressure (IOP) remains the only reliable modifiable risk factor to date and thus treatment modalities are aimed at reducing IOP by pharmacological, laser, or surgical means.¹ Although elevated IOP, defined as >21 mmHg, is a risk factor for glaucoma, approximately one-third of patients, with even higher rates in some populations, develop glaucoma without having a documented history of IOP of greater than 21 mmHg.⁶ Patients who develop glaucoma despite IOP within the “normal” range are said to have low-tension glaucoma (LTG) or normal-tension glaucoma.

Etiology

The exact etiology of LTG in comparison to other forms of open-angle glaucomas, including primary open-angle glaucoma (POAG), remains to be answered. Despite being on a spectrum, it has been suggested IOP is the primary driver of disease in POAG, while systemic risk factors are as important or potentially even more important for disease onset and progression in LTG.⁷ In the treatment arm of the Collaborative Normal Tension Glaucoma Study (CNTGS), IOP was reduced 30% from baseline. Although the treatment group fared better at 3 years, there was visual field loss in both groups.⁸ This suggested that while IOP reduction is important in LTG, other risk factors for progression may exist.^1,3,8

Although there is disagreement whether LTG and POAG are truly distinct phenotypes, certain distinctive features of LTG exist. In comparison to other types of glaucoma characterized by elevated IOP, the visual field deficits in LTG tend to be closer to fixation, possibly due to different populations of ganglion cells and axons being more sensitive to IOP.^3,9 Furthermore, on examination, the optic disc often demonstrates deep notches, neuroretinal rim thinning that is out of proportion to the amount of visual field loss, disc hemorrhages, and beta peripapillary atrophy.^10,11 In addition, although LTG may affect any patient, certain demographic risk factors including race and female gender exist.¹² Despite the differences in patient demographics and clinical features, treatment modalities for LTG and POAG remain similar — namely, IOP reduction.

Monitoring and Treatment

Incisional procedures are indicated for patients with LTG if medical therapy and trabeculoplasty are not successful when low target pressures are required.¹¹ The CNTGS recommended a 30% initial IOP reduction, which slowed progression in patients with LTG.⁸ This is a similar strategy used in other types of glaucoma characterized by elevated IOP. For drop therapy, the Low-pressure Glaucoma Treatment Study suggested utilizing brimonidine in patients with LTG since the brimonidine group was less likely to have visual field progression at 30 months in comparison to the timolol group, despite similar IOP reductions.¹³ Potential explanations include direct neuroprotective effects from brimonidine or negative effects from a topical beta blocker that may further diminish optic nerve perfusion.¹³ Though not the mainstay of therapy or constantly reliable, treatment for LTG in some cases may include optimization of cardiovascular risk factors that may affect optic nerve head perfusion. This includes avoiding systemic hypotension through the reduction of systemic antihypertensive medications or avoidance of nocturnal dosing as well as the use of positive pressure ventilation in patients with obstructive sleep apnea.¹⁴

LTG prevalence has varied depending on the patient population, suggesting a differential sensitivity of the retinal ganglion cell in certain patient populations related to genetics, ocular risk factors, or environment. For example, approximately 1/3 of open-angle glaucoma patients have LTG in Caucasian populations within the United States,¹⁵ while this number is nearly 60% in a Zulu population in South Africa,¹⁶ and is as high as 90% in Japan.¹⁷

Several factors unrelated to IOP or indirectly related to IOP have been proposed to explain the apparent difference in susceptibility of retinal ganglion cells to measured IOP. For example, translaminar pressure gradient, or the pressure differential of IOP and intracranial pressure (ICP), attempts to quantify the perceived stress on the optic nerve at the lamina cribrosa and may play a role in the pathophysiology of retinal ganglion cell loss. A low ICP may lead to increased stress on the optic nerve at the lamina cribrosa at a given IOP. In support of this theory, patients with LTG have demonstrated lower opening pressures on lumbar puncture and thus higher translaminar pressures than controls or POAG patients with elevated IOP.¹⁸

There are challenges in accurately measuring IOP in different patient populations and variations in corneal biomechanics. Goldman applanation tonometry (GAT) is currently the gold standard for measurement of IOP.¹⁹ However, GAT is limited by corneal irregularities, external pressures on the globe, and corneal scars and edema.²⁰ In addition, GAT is calibrated at the CCT of 520 μm^19,20; therefore, if CCT is greater than 520 μm then IOP will be overestimated, while if it is less than 520 μm it will be underestimated.²¹ Furthermore, patients who have undergone ablative procedures such as laser-assisted in-situ keratomileusis (LASIK) have decreased CCT, thus having lower measured IOP.¹⁹ Measured IOP reduction is approximately 1 mmHg per 1 diopter corrected during refractive surgery.²² Therefore, it is important to identify patients with thin corneas in which IOP will be underestimated.

An additional contributor to the perceived stress of the retinal ganglion cell at a given IOP is the status of optic nerve perfusion. The vascular hypothesis of glaucoma suggests that a reduction in the peripapillary microcirculation and ocular perfusion pressure (OPP) plays a significant role in retinal ganglion cell death and atrophy.²³ OPP is directly related to mean arterial systemic blood pressure and inversely proportional to IOP. Therefore, either lower mean arterial pressure or increased IOP would lead to diminished OPP and potential retinal ganglion cell stress.²⁴ In further support of this hypothesis, low systemic blood pressure and nocturnal hypotension have been associated with LTG.²⁵

Studying Low-tension Glaucoma

We recently completed a retrospective case-control study of patients with LTG to identify systemic risk factors associated with LTG. There were 277 patients enrolled in the LTG group and 277 patients in an age-matched and sex-matched control group.¹ In addition, LTG patients were separated in two metabolic phenotypes. Phenotype 1 was a LTG patient with risk factors associated with metabolic syndrome and related findings including systemic hypertension, diabetes mellitus, peripheral vascular disease, coronary artery disease, and obstructive sleep apnea (OSA). Phenotype 2 was a LTG patient with Raynaud syndrome, migraine headache, anemia, or systemic hypotension. Although there was no significant difference in body mass index (BMI) compared to the control group, LTG patients were more likely to have a BMI within the healthy range while the control group was more likely to have a BMI in the obese range.¹

There were multiple systemic vascular risk factors that demonstrated a significant risk for LTG compared to the control group, including systemic hypertension, diabetes mellitus, peripheral vascular disease, migraine headache, anemia, systemic hypotension, and Raynaud’s syndrome. Our data suggested that other potential risk factors — including dyslipidemia, coronary artery disease, stroke, carotid stenosis, OSA, lupus, alcohol history, or smoking history — did not play a role. In terms of medication risk factors, after controlling for systemic hypertension, of the anti-hypertensive medications calcium channel blocker usage was associated with LTG.¹

Our study supported the vascular hypothesis of glaucoma as there were multiple systemic vascular risk factors that were significantly associated with LTG. One interesting finding was the parabolic relationship between blood pressure and LTG as both systemic hypotension and hypertension were risk factors.¹ We hypothesized that the risk factors of Raynaud’s syndrome, migraine headache, peripheral vascular disease, and anemia were likely secondary to diminished OPP, either secondary to vasospasm or a reduction in oxygen-carrying capacity that can cause retinal ganglion cell stress and eventually atrophy and death.¹

Conclusion

Low-tension glaucoma has distinctive features and risk factors compared to POAG. Whether there are truly IOP-independent stresses on the retinal ganglion cell or retinal ganglion cell stresses disproportionate to the measured IOP remain to be determined. Nevertheless, at present, IOP reduction remains the mainstay of therapy. Avoidance of hypoxic events that lead to optic nerve hypoperfusion may be helpful adjunctive interventions for the reduction of progression of glaucoma. Further studies are needed to determine whether other risk factures, including those that are vascular in nature, may alter risk of glaucoma progression when treated. GP

Tyler M. Kaplan, MD, is an ophthalmology resident at the Mayo Clinic in Rochester, Minnesota.

Gavin W. Roddy MD, PhD, is a professor of ophthalmology at the Mayo Clinic. They report no relevant disclosures. Reach Dr. Roddy at Roddy.Gavin@mayo.edu.

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