Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells, leading to vision impairment and/or blindness.1 Glaucoma is the second leading cause of blindness worldwide, affecting more than 80 million people.2,3 In Japan, normal-tension (or low-tension) glaucoma accounts for 92% of open-angle glaucoma diagnoses.4
Mechanical vs. vascular theories for NTG
Both mechanical and vascular theories are considered as possible pathogenic mechanisms in the development of glaucoma. The mechanical theory believes that elevated intraocular pressure (IOP) causes optic disc cupping and visual field loss due to retinal ganglion cell damage.5 The mechanical theory does not apply to normal-tension glaucoma (NTG) as much as other subsets of glaucoma, as it is a pressure-independent glaucoma.
The vascular theory posits that chronic ischemic and vascular dysregulation lead to loss of retinal ganglion cells. Vascular dysregulation is suggested to be a main factor in the pathophysiology of NTG. There are risk factors that play a role in developing NTG due to vascular dysregulation, such as migraine headache, Raynaud’s syndrome, peripheral vascular disease, and anemia.5
NTG risk factors
- Migraine: Migraine headaches are presumed to be associated with vascular dysregulation resulting in poor blood flow at the optic nerve head, increasing susceptibility to glaucomatous damage.
- Raynaud’s syndrome: This is caused by peripheral vasospasm, which can lead to dysregulation of peripheral perfusion. It has been suggested to be an independent risk factor for the development of NTG.6
- Anemia: By decreasing the oxygen-carrying capacity of the blood, this may ultimately lead to retinal ganglion cell stress, atrophy, and ultimately death.7
- Obstructive sleep apnea: This may cause hypoperfusion to the optic nerve head and glaucomatous optic neuropathy by creating transient hypoxemia and increasing vascular resistance.8
- Low diastolic blood pressure: This represents a state of cardiovascular autonomic dysregulation, resulting in low ocular perfusion in certain NTG patients.9 Low nocturnal blood pressure especially has a higher association in those with NTG.10,11
- Hypotension causes low ocular perfusion pressure and reduces ocular blood flow, ultimately reducing blood flow to the optic nerve. This is important to consider in nocturnal blood pressure “dippers,” or when blood pressure drops more than ≥ 10% at nighttime.10,12
- Ocular perfusion pressure (OPP): The Early Manifest Glaucoma Trial (EMGT) showed that a low systolic OPP was a prognosticator of worsening of glaucoma, with a hazard ratio of 1.42.13
- The Egna-Neumarkt Study found an increased risk of open-angle glaucoma with a diastolic OPP < 50mmHg.14
Additional factors influencing NTG
Three other factors have a major influence on the development of NTG, including cerebrospinal fluid, genetics, and gender.
Cerebrospinal fluid
Recent studies have shown biomechanical factors that may influence the optic nerve head’s vulnerability to pressure. Glaucomatous damage occurs at the lamina cribrosa, the boundary between the optic nerve interstitial pressure, retrobulbar cerebrospinal fluid pressure (retrolaminar compartment), and intravitreal IOP.15-18
NTG patients tend to have a lower cerebrospinal fluid pressure (CSFP) compared to the normal population.17,19 Decreased CSFP may lead to higher translaminar pressure, ultimately leading to optic nerve damage due to changes in axonal transport, deformation of the lamina cribrosa, and altered blood flow, leading to glaucomatous damage.20
Genetics
A positive family history of glaucoma is a risk factor. Genes such as optineurin (OPTN), myocilin (MYOC), tank-binding protein 1 (TBK1) are associated with NTG.21
Female gender
Being of female gender is an associated risk factor for NTG.22 It is theorized that this is due to the prevalence of primary vascular dysregulation being higher in women than men.23
Differential diagnosis of NTG
Differential diagnoses to NTG include primary open-angle glaucoma (POAG) and ischemic optic neuropathy due to optic nerve cupping and visual field loss.
Key findings on the clinical examination can help distinguish these diagnoses:
- IOP: NTG has been defined as glaucomatous optic neuropathy with IOP measurements consistently < 21mmHg.24
- Visual field: Those with NTG tend to have visual field defects that are more localized, deeper, and central compared to POAG.25
- Visual field defects in other optic neuropathies may vary, for example, arteritic ischemic optic neuropathy will present with a dense altitudinal defect or diffuse loss in the affected eye.
- Optic nerve: Both NTG and POAG will display similar morphological features, such as thinning of the neuroretinal rim and a large cup-to-disc ratio. However, compared to POAG, those with NTG tend to have a larger cup-to-disc ratio and a thinner neuroretinal rim.25,26
- Pallor is not typically noted in glaucoma, and if this is noted, suspect a non-glaucomatous optic neuropathy.
- Disc hemorrhage: This is considered to be a significant risk factor associated with glaucomatous progression, noted by visual field deterioration and retinal nerve fiber layer thinning.27 Disc hemorrhages are more prevalent in those with NTG compared to POAG.28
Gonioscopy
Both NTG and POAG will present with open angles on gonioscopy.
Pachymetry
Thin central corneal thickness (< 545µm) is a risk factor for the development of glaucoma. Those with NTG tend to have a lower central corneal thickness compared to POAG patients.29,30
OCT RNFL
Optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) analysis offers a quantitative estimation of retinal ganglion cell loss. This tool allows for screening and progression analysis of patients with optic nerve diseases, such as glaucoma.
Studies have had varying results, with some suggesting that NTG exhibits greater RNFL loss compared to POAG, while other studies found no significant difference between the two.31,32
Figure 1: OCT RNFL analysis OD of a patient with NTG, note the temporal RNFL thinning and paracentral/ganglion cell complex defects.
Figure 1: Courtesy of Justin Schweitzer, OD, FAAO.
GCL–IPL scan
The ganglion cell layer gives rise to axons that compose the RNFL and optic nerve. Thus, thinning on a ganglion cell layer–inner plexiform layer thickness (GCL–IPL) scan is often positively correlated with vision loss corresponding with visual field sensitivity from glaucoma or changes before noted on a visual field.
Studies have found that GCL–IPL loss is more localized in NTG patients compared to diffuse loss in POAG.33
OCT angiography
This non-invasive technique allows for in vivo evaluation of retinal vasculature. This enables practitioners to view decreased optic disc perfusion in glaucoma patients, indicating optic disc ischemia and glaucoma.
Peripapillary vessel density will be lower in POAG eyes compared to NTG eyes, possibly due to the IOP-induced stress and strain of the optic nerve head.34
Management of normal-tension glaucoma
The recommended management of NTG is to lower the IOP. The Normal-Tension Glaucoma Trial demonstrated the benefit of lowering the IOP; however, some patients are more IOP-sensitive than others, as 20% of the treated patients continued to progress.35
The Collaborative Normal Tension Glaucoma Study (CNGTS), a prospective randomized clinical trial, also demonstrated the effect of IOP lowering in those with NTG. One eye was randomized to either no treatment as a control or medical, laser, and/or surgical intervention to lower the IOP by 30% from baseline. A 30% reduction in IOP reduced the risk of progression from 35 to 12%.36
Pharmacological therapies
Glaucoma drops such as prostaglandin analogs, beta-blockers, carbonic anhydrase inhibitors, alpha agonists, and rho kinase inhibitors are recommended in the treatment and management of NTG.
Surgical
When the IOP can no longer be adequately controlled by medication or patients are non-compliant with medical therapy, surgical options may be appropriate. Options such as laser trabeculoplasty, trabeculectomy, aqueous shunts, and microinvasive glaucoma surgery (MIGS) are available to NTG patients.
Advances in diagnostics and interventions for NTG
There is mixed evidence regarding calcium channel blockers for the treatment of glaucoma. Some studies showed a neuroprotective effect in NTG patients. Other studies showed that while there is a decrease in the IOP, the peripheral vasodilation may cause systemic hypotension and lower diastolic OPP to the optic nerve, which may induce further damage.37
Serum anti-SSA and anti-SSB antibody levels were found to be higher in NTG patients compared to POAG. Anti-SSA/SSB are commonly seen in autoimmune diseases, such as Lupus and Sjögren’s syndrome.38 These findings suggest autoimmunity mechanisms that may play a role in NTG.39 Additionally, NTG patients have been found to have alterations of the autoantibody pattern of heat shock proteins (HSPs).39
HSPs have been identified as stress proteins against thermal stress and under physiological conditions. HSPs may also be expressed when induced by internal and external stimuli such as heat, inflammation, oxidative stress, and toxic substances.40 It is believed that autoantibodies against HSPs in glaucoma patients could be involved in the disease onset and progression.
Final thoughts
Normal-tension glaucoma can be a challenging subset of glaucoma to diagnose and manage. There are key IOP-independent risk factors leading to its pathogenesis, such as vasospasm and OPP.
Ultimately, lowering of the IOP is the most effective treatment for preventing further visual impairment for NTG patients.
