Continuing Education Activity

Normal-tension glaucoma is a characteristic glaucomatous optic neuropathy with intraocular pressures in the normal range. It is a common condition and can lead to bilateral blindness. Monitoring and treatment can reduce the risk of visual morbidity in most patients. This activity reviews the evaluation and management of normal-tension glaucoma and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the risk factors for developing normal-tension glaucoma.
• Assess the physical exam findings associated with normal-tension glaucoma.
• Evaluate management considerations for patients with normal-tension glaucoma.

Introduction

Glaucoma is characteristic of progressive optic neuropathy, featuring optic disc cupping and visual field loss, associated with raised intraocular pressure (IOP). Normal-tension glaucoma (NTG), also known as normal or low-pressure glaucoma, is open-angle with a presenting IOP in the normal range.[1] The pathogenesis remains poorly understood, and there is controversy over whether it is a spectrum of primary open-angle glaucoma (POAG) or represents heterogeneous diseases. The impact of NTG can range from non-progressive, asymptomatic disease to bilateral blindness. An impaired visual field leading to the loss of a driver's license can significantly impact quality of life. Adverse effects and costs of medical and surgical treatments should be weighed against the risk of visual loss. NTG can masquerade as other optic neuropathies, and care should be taken to investigate other causes when indicated adequately.

Etiology

A variety of mechanisms have been proposed to explain the pathogenesis of NTG. Whereas IOP is the main driver of progressive visual loss in most patients with POAG, NTG likely represents a heterogeneous or multifactorial group of etiologies with a common final pathway of retinal ganglion cell loss. Despite IOP in the statistically normal range, there is evidence that an IOP-dependent mechanism plays a role in the etiology in many eyes with NTG.[2][3] Proposed IOP-independent mechanisms include vascular insufficiency at the optic nerve head, metabolic and neurodegenerative disorders, oxidative stress, and abnormal biomechanics of the lamina cribrosa.[4] Genetics is known to play a role because of the strong association with family history and variation in prevalence in different ethnicities that persists after migration. Three Mendelian genes have been associated with NTG but are rare even among patients with NTG and are more likely in those with an early onset and strong family history of NTG.[5] 

Genes associated with NTG:

• Optineurin (OPTN)
• TANK binding kinase (TBK1)
• Myocilin (MYOC)

Risk factors for NTG:

• Age
• Family history
• Female gender
• Above-average IOP
• Thin central corneal thickness
• Systemic hypertension
• Nocturnal hypotension
• Migraine
• Raynaud phenomenon
• Frontotemporal and Alzheimer dementia
• Obstructive sleep apnea[3][6][7][8]

Epidemiology

The prevalence of NTG varies significantly by ethnicity. The population prevalence of POAG in East Asian countries is reportedly between 1 and 4%. However, NTG comprises up to 95% of these cases.[9][10] The prevalence of POAG among white European populations is approximately 2%, but only around one-third are NTG,[11][12] with higher prevalences (3 to 8%) and proportions (around 50%) of NTG in sub-Saharan African populations.[13][14] The disease burden from POAG and NTG is expected to increase with increasing life expectancy. IOP normal ranges are defined by population IOP studies in healthy subjects, with an interval of 2 standard deviations from the mean. Approximately 95% of normal subjects will have an IOP between 11 and 21mmHg.[15] Therefore, a cut-off of 21mmHg is often applied to define NTG.

Pathophysiology

The histopathological changes in NTG are the same as those found in POAG, namely loss of retinal ganglion cell axons (retinal nerve fiber layer - RNFL) and glial tissue at the optic nerve head, leading to optic disc excavation and cupping.[16] Typically, RNFL loss is more common in the supero- and inferotemporal neuroretinal bundles, leading to notches, but loss may also be global and concentric. Some changes are more common in NTG than in POAG. These include Drance hemorrhages and temporal RNFL defects, with localized, deep paracentral scotomas, more often in the superior hemifield.[17][18]

History and Physical

Patients are usually asymptomatic at presentation, with suspicion of glaucoma raised by an optometrist on routine eye testing or an incidental finding with an ophthalmologist.[19] Even with moderately advanced disease, patients may be unaware of field defects because of unilateral disease, negative scotoma, and gradual onset. Because the IOP is normal, suspicion is usually roused by optic disc appearance or a visual field defect on automated perimetry. If the presentation is advanced, patients may have symptoms of reduced vision, difficulty with low-contrast situations, and awareness of visual field defects. They may experience glare and difficulty adjusting to extreme lighting conditions. A family history of glaucoma and blindness should be obtained. Past medical history should include assessing risk factors for glaucoma, such as the history of steroid use, ocular trauma or surgery, and contraindications to treatments, including allergies. Medication usage should be reviewed.

A relative afferent pupillary defect is typical, though it may not be present in the early or symmetrical disease. Color vision is usually preserved, except in advanced disease. By definition, the IOP is in the normal range.[20] Slit-lamp examination and gonioscopy are essential to determine an open iridocorneal angle status and exclude secondary glaucoma causes. In particular, evidence of angle closure, uveitis, pigment dispersion, and pseudoexfoliation syndrome should be sought, as these are common causes of glaucoma presenting with an IOP in the normal range. A dilated fundus examination revealed changes in the glaucomatous optic disc. There is a progressive loss of ganglion cell neurons, leading to enlargement of the cup-to-disc ratio. This may be a focal (notch, retinal nerve fiber layer (RNFL) defect) or concentric defect (excavation, senile sclerotic disc). Disc pallor occurs in advanced disease. Measurement of the optic disc size can help identify hypoplasia, physiological disc cupping, and disc asymmetry. Optic disc hemorrhages are more common in NTG than in POAG.[6] So-called Drance hemorrhages are typically small flame hemorrhages at the disc margin in superior or inferior quadrants. Peripapillary atrophy may be seen but is non-specific. Glaucomatous disc abnormalities typically precede visual field defects in early (preperimetric) disease.[21]

Evaluation

Automated perimetry, particularly the Humphrey 24-2 visual field, is the most common algorithm for monitoring glaucoma, including NTG. Alternatively, 10-2 fields (especially in advanced disease) and wide-field exams (30-2 and Estermann) can be employed.[22] SITA fast and faster algorithms shorten test duration, achieving similar accuracies.[23] Stereoscopic fundus photos of the optic nerve head at presentation provide a baseline comparison for future fundus examinations. The photos can be repeated to document change. OCT technology has revolutionized the monitoring of glaucoma. Various methods are commonly used but have variations between imaging platforms. All measurements of ganglion cell neuron layers are compared against a normative database calibrated for the device. OCT helps determine a healthy optic nerve structure or document structural progression on serial scans.[24][25] Corneal pachymetry is used to measure the central corneal thickness (CCT). Reduced CCT is associated with progression risk. Thinner corneas are associated with the underestimation of intraocular pressure using applanation tonometry.[26] However, other factors such as corneal hysteresis also contribute to measurement error in applanation tonometry.[27] Larger than normal diurnal variations in IOP are seen in POAG and NTG, with the highest pressures typically in the early morning.[28] IOP phasing is repeated IOP measurements, measured throughout the day during office hours or at home over 24 hours with a home rebound tonometry device. IOP phasing can help demonstrate an IOP mechanism in patients with rapidly progressive disease, with apparently controlled IOP measured in the office. An alternative method to simulate labile IOP in the office is the water-drinking test.[29]

Treatment / Management

Not all eyes with NTG will progress to clinically significant vision loss. In the Collaborative Normal-Tension Glaucoma Study (CNTGS), 65% of eyes without treatment showed no progression over five years.[30] Monitoring a patient without treatment is a suitable initial management strategy in many cases but requires discussion with the patient. IOP lowering treatment should be instituted if there are confirmed progressive changes of the optic disc or visual field, and such progression is likely to lead to visual morbidity in their lifetime. Optic disc hemorrhages are also often interpreted as a marker of disease progression.[31][32] Treatment at diagnosis may also be recommended in eyes with moderate or advanced disease, paracentral visual field defects that threaten fixation, and those with multiple risk factors for blindness. Once progression has been demonstrated, CNTGS showed an aggressive IOP lowering of 30%, leading to a slower visual field loss rate. However, 12% of the treated group still progressed despite aggressive treatment.[30] The presumed benefit of escalating treatment should always be weighed against each patient's risks and side effects.

IOP lowering is the only known modifiable risk factor that alters disease progression in POAG and NTG. Strategies include topical IOP lowering medications, laser treatments such as selective laser trabeculoplasty (SLT) or cyclodiode laser, and drainage surgery. The role of micro-invasive glaucoma surgeries (MIGS) remains controversial. Prostaglandin analogs are a common first-line therapy. A comparison of topical brimonidine and timolol showed similar IOP lowering but less progression with brimonidine.[33] It is hypothesized that brimonidine may have an additional neuroprotective effect. Studies have shown that SLT can still have a pressure-lowering effect in the normal range. In eyes with continued progression or very low pressure (less than 12mmHg) requiring treatment, surgical management with augmented trabeculectomy is likely required to achieve optimal IOP lowering. In the latter case, postoperative IOP below 10mmHg has been shown to eliminate VF progression.[34][35][34] No IOP-independent treatments have been proven to alter disease progression; however, non-IOP risk factors are being investigated to understand better their role in the pathogenesis of NTG and their feasibility as interventions. In patients with these risk factors or progressive disease despite IOP treatment, treatment could be considered. These risk factors include:

• Nocturnal hypotension – It is hypothesized that this causes reduced perfusion pressure at the optic nerve head. A 24-hour blood pressure analysis and avoiding nighttime dosing of systemic anti-hypertensives can be considered.[36]
• Diet and nutritional supplementation – Nicotinamide (vitamin B3) and ginkgo biloba are under investigation.[37][38]
• Obstructive sleep apnoea – This is hypothesized to alter optic nerve perfusion pressure. Screening questions for this disease can be asked to identify patients at risk.[39]
• Exercise – Regular exercise is associated with lower IOP afterward, but a positive or negative effect on the pathogenesis of NTG is unknown.[40][41] Exercise is beneficial for many other aspects of health and should not be discouraged. Even in those with severe sight loss, supporting safe exercise likely helps the person holistically. However, yoga positions held for extended periods that position the eye below the rest of the body (such as headstands or downward dog) can significantly raise intraocular pressure, and case studies have shown rapidly progressive disease.[42]
• Meditation – A randomized-controlled trial showed mindfulness meditation could lower IOP, reduce IOP fluctuation, and positively affect neuroprotective markers.[43][44][43]
• Cannabinoids – These have been shown to reduce IOP, but not in a clinically meaningful way.[45] Cannabinoids are not currently recommended as a treatment for glaucoma.
• Smoking – Smoking may be associated with both raised IOP and glaucoma.[46]

Differential Diagnosis

Alternate subtypes of glaucomas are the most common considerations in the differential diagnosis and may present with normal IOP. These include:

• Angle-closure glaucoma
• Hypertensive uveitis
• Pigmentary glaucoma
• Pseudoexfoliative glaucoma
• POAG with thin central corneas, underestimating the true IOP.

Previous episodes of raised IOP, including a history of ocular trauma, hyphema, steroid use, or vitrectomy. Previous vascular insults or compromise can cause a non-progressive picture similar to NTG. These include retinal vascular occlusions, arteritic or non-arteritic anterior ischaemic optic neuropathy, and severe systemic hypotension (eg, after surgery, trauma, or sepsis). Non-progressive disc abnormalities that may be misdiagnosed as NTG include physiological disc cupping, tilted discs, myopic fundus, disc drusen, optic disc pit, or congenital anomalies such as optic disc coloboma or superior segmental optic nerve hypoplasia. Other optic neuropathies, including optic neuritis and hereditary, toxic, traumatic, and inflammatory optic neuropathies, may be considered. Intraorbital or intracranial tumors, including pituitary adenomas, are an important differential. Red flags include young age without a family history, rapid progression, unilateral disease, proptosis, associated neurological symptoms or signs, atypical disc findings, such as disc pallor without cupping, or field defects that respect the vertical midline. In the presence of these red flags, contrast-enhanced MRI of the anterior visual pathway is indicated to exclude compressive lesions.

Prognosis

NTG can progress to bilateral blindness in the worst cases, sometimes despite treatment. However, not all patients progress to visual morbidity. On average, progression is slower in NTG than in POAG. Those at higher risk of visual field progression are females and those with a history of migraines, the presence of optic disc hemorrhages, and greater variation in diurnal IOP.[30][47][7] Patients who present with advanced disease or rapidly progressing visual field loss are most likely to be blinded by the condition, and these so-called ‘rapid progressors’ should be identified and treated more aggressively.[48]

Complications

Morbidity from vision loss in NTG can be significant and lead to difficulty with activities of daily living (ADL). Tasks that involve visual searching are commonly affected, and fall risk increases.[49][50][51][52] On the other hand, asymmetric disease may preserve the ability to perform ADLs, even with a severe loss in one eye. Paracentral defects are more common in NTG, so there is a higher risk of developing a central defect on binocular visual field testing.[53] In many countries, licensing rules would exclude them from driving.[54][55] However, professional drivers or pilots may lose their license with only a relatively mild disease in one eye.

Conjunctival hyperemia and ocular surface symptoms are the most common side effects seen with all classes of topical IOP-lowering medications. Side effects of prostaglandin analogs include hypertrichosis and changes in iris pigmentation. Prostaglandin-associated periorbitopathy is an important complication of long-term prostaglandin analog use. This includes orbital fat atrophy, ptosis, chronic inflammation of the eyelids, and skin discoloration. It is seen most commonly with bimatoprost.[56][57] In addition, filtration surgery may have lower success rates in these patients. Topical beta-blockers are relatively contraindicated in patients with asthma and COPD. Additional systemic side effects include cardiovascular effects, vivid dreams, erectile dysfunction, and mood changes. Carbonic anhydrase inhibitors should be used with caution in those with a history of sulfonamide allergy. Alpha-agonists are contraindicated in young children. Complications from SLT are rare but may include intraocular inflammation or an IOP spike after treatment. Glaucoma surgery complications include failure, hypotony, cataracts, phlebitis, tube erosion, endophthalmitis, and corneal decompensation.

Consultations

The psychological burden of having an incurable, potentially blinding condition should not be underestimated.[58] Even asymptomatic patients who are only being monitored for a suspicious optic disc appearance can experience a negative impact on their general well-being. In addition, the side effects of treatment can impair quality of life. For some patients and their families, the cost of treatment or attending the clinic can be challenging. Tailored treatment strategies should be weighed against an individual risk assessment of patients experiencing visual morbidity in their lifetime. The interprofessional team should routinely create opportunities for patients to raise concerns and comfortably discuss their desired treatment goals. A personalized approach to treatment and monitoring can thereby be delivered.

Deterrence and Patient Education

Glaucoma is the second most common cause of irreversible blindness worldwide and is a public health concern in both the developed and developing world.[59] Early detection is challenging due to the lack of symptoms. Various public health measures, including population screening, have been considered to try and reduce the burden of patients presenting with advanced disease. Educating the public on the importance of regular eye exams facilitates the detection of NTG and other eye diseases.[19] Patients who are diagnosed with glaucoma should be instructed to advise first-degree relatives to have regular eye exams to enable early detection.[60]

Enhancing Healthcare Team Outcomes

As individuals live longer, society is increasingly burdened by age-associated eye disease. This includes glaucoma, where many countries have a shortage of specialists, necessitating innovative methods to meet the needs of patients. This includes refined referral pathways, virtual clinics, artificial intelligence, community-based clinics, and training of allied health professionals in delivering patient care independently or as part of a consultant-led team. Glaucoma is a chronic condition, and utilizing the communication skills of nursing and allied health staff in educating and training patients can improve patient understanding and treatment concordance. For those with glaucoma-related vision loss, low vision clinics can maximize remaining vision and help patients adapt to their disability. Local and national societies can provide patients with peer support and opportunities for collaboration between healthcare providers and patient groups. Health professionals should be advocates for their patients to enable access to the treatments and services needed in their area.

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Disclosure: Daniel Gosling declares no relevant financial relationships with ineligible companies.

Disclosure: Jay Meyer declares no relevant financial relationships with ineligible companies.