Major Risk Factors in Primary Open-Angle Glaucoma

Glaucoma continues to be an international health issue with an estimated 111 million people having glaucoma by 2040.¹ Due to its asymptomatic nature, risk of irreversible blindness, and difficulty in diagnosis, clinicians must continue to be vigilant in identifying glaucoma patients and glaucoma suspects based on risk factors.

What is open-angle glaucoma?

Glaucoma is a group of optic neuropathies characterized by progressive retinal ganglion cell (RGC) atrophy with resultant distinctive structural and functional damage to the optic nerve.² For the purposes of this article, we will focus on primary open-angle glaucoma (POAG). Though IOP is the only treatable risk factor in POAG patients,³ the clinician must be aware and properly identify a multitude of risk factors in the assessment of every glaucoma patient or suspect.

It is helpful to mentally separate these into the categories of non-ocular and ocular risk factors.

Ways to measure IOP in glaucoma patients

In this video, Dr. Holly Swain talks about the standard and new ways to measure intraocular pressure in glaucoma management.

Non-ocular risk factors of primary open-angle glaucoma

Age: Patients over 60 years old are at greatest risk of glaucoma, with risk increasing with advancing age. Patients as young as 40 years old may be at risk of glaucoma, especially if they are of African descent or have a strong family history.²
Race: Studies indicate that African Americans have a six times higher risk of developing glaucoma than Caucasians, and the onset of glaucoma is ten years earlier in African Americans than in Caucasians. Hispanics and Asians are also at an increased risk for glaucoma compared to Caucasians.⁴
Gender: There is no clear gender predilection.⁵
Family history: Approximately 60% of glaucoma patients have at least one family member who also has glaucoma.⁴ Having a first-degree relative (immediate family member) with open-angle glaucoma (primary or secondary) increases a person’s lifetime risk of developing glaucoma from 2.3% to 22%.4 Having a sibling with glaucoma increases one’s risk from 0.7% to 10.4%.⁴
Systemic conditions

Systemic conditions that increase glaucoma risk

Multiple systemic conditions can increase one’s risk for glaucoma, including.

Diabetes: Multiple case-control studies and population-based cohort studies indicate diabetes likely increases the risk of glaucoma.⁶
Hypertension: The association between blood pressure and glaucoma has been found in numerous studies. The Blue Mountains Eye Study found that increased systolic blood pressure is linked to increased IOP. Other studies have suggested that low diastolic pressure may be associated with glaucoma.⁴
Migraine: An increased risk for open-angle glaucoma (primary and secondary) has been found in those with migraines, but only for those aged 70-79.⁷ Another study indicated that a history of migraines is more common in patients with any form of glaucoma.⁸
Vasopasm: Peripheral vasospasm has been listed in some studies as a risk factor for normal tension glaucoma (NTG).⁴
Obstructive sleep apnea: Obstructive sleep apnea has been associated with glaucoma in some studies. However, more research is needed to confirm if it is indeed an independent risk factor.^9,10

Ocular risk factors of glaucoma

The following are ocular risk factors which may lead to the progression or worsening of glaucoma.

Myopia

Increased axial length and myopia have both been found to be risk factors for open-angle glaucoma. It has been suggested that this risk increases with increased myopia.⁴

IOP

It is well established that elevated IOP is a risk factor for glaucoma. One result of the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study is the development of risk calculators for patients with increased IOP.

Pachymetry

The OHTS investigators found that those with CCTs ≤555μm had three times the risk of progressing POAG than those with CCTs >558μm. Also, the risk of progressing to POAG doubled for every 40 μm decrease in CCT from the mean of 573.3μm.^11-14

Angles

When considering a diagnosis of open-angle glaucoma, it would be a good idea to confirm that the angles are indeed open via gonioscopy and/or anterior segment OCT. Be sure to assess for psuedoexfoliation, angle recession, neovascularization, etc. to exclude secondary open-angle glaucoma.

Optic nerve

C/D: A normal C/D ratio is typically between 0.30 and 0.50. However, if the optic nerve head itself is smaller or larger, then the C/D ratio should be expected to be correspondingly smaller or larger. Therefore, an average C/D ratio in a small disc is not necessarily comforting, but a large C/D ratio in a large disc is not necessarily concerning.

Also, keep in mind the ISNT rule. The ISNT rule states that the neuroretinal rim should appear thickest to thinnest, inferiorly, superiorly, nasally, and temporally. Asymmetry between the two eyes of more than 0.20 may indicate early glaucoma.¹⁵

Nerve

Glaucomatous damage may present with a deepening of the cup, exposed lamina cribrosa (seen as laminar dots), sloping of the disc margins, focal cup excavation, and/or bean potting (seen by a break in the pathway of the vasculature at the optic cup margin).¹⁶

Peripapillary atrophy (PPA)

PPA appears in two regions: beta zone, which is a crescent-shaped area located adjacent to the optic nerve, and alpha zone, which is located beyond beta zone in relation to the optic nerve head. Beta zone PPA is a chorioscleral crescent representing atrophy of the RPE and choriocapillaris. It is hypopigmented and corresponds with an absolute scotoma.¹⁷

Alpha zone peripapillary atrophy (PPA) is a crescent of hyperpigmented irregularities in the RPE and corresponds with a relative scotoma.¹⁷ Alpha zone PPA may be present in normal and glaucomatous eyes. Beta zone PPA is more common in glaucoma, but it may be present in up to 20% of normal patients.^15,17

Retinal nerve fiber layer (RNFL)

RNFL defects appear as dark striations or reduced brightness in the peripapillary area. They are typically wedge-shaped and located superiorly and inferiorly. It is believed that these RNFL defects represent the loss of axon bundles. This atrophy typically precedes field loss.¹⁵

Vascular

Disc hemorrhages can be within 1 disc diameter of the optic nerve head and are typically splinter or flame shaped. Their presence is rare in normal eyes and is highly suggestive of glaucoma. Nasalization of the central vessels, baring of the circumlinear vessels, vessel bayoneting, and vessel overpass are each indicative of glaucoma.¹⁵ Nasalization refers to the central vessels being displaced nasally.

Baring is characterized by the circumlinear vessels becoming more exposed by receding of the cup. The typically indistinct thin circumlinear vessel borders become more distinct as this occurs. Bayonetting describes a sudden angular change as the vessel traverses the rim.

Visual fields

When glaucoma is suspected, the most commonly used perimetry technique is standard automated perimetry (SAP). It is generally considered to be the best method of monitoring glaucoma patients for functional changes. It has been suggested that Short Wavelength Automated Perimetry (SWAP) may detect glaucomatous field loss 3-5 years before SAP. However, this is controversial, and SWAP is not often used.

The Matrix Frequency Doubling Technology (FDT) has been shown to be superior at detecting early glaucomatous changes.¹⁸ It is thought that FDT accomplishes earlier detection by preferentially stimulating the retinal ganglion cells of the magnocellular pathway. Whatever perimetry machine is used, the 24-2 testing pattern is typically utilized. This tests the central 24 degrees and two nasal locations that are 30 degrees from fixation.

The SITA Standard and the Matrix FDT each take about 5 to 10 minutes per eye. Though SITA Standard is considered the gold standard perimetric protocol for glaucoma patients, newer protocols such SITA Fast and SITA Faster have been developed to decrease test taking time without sacrificing significant clinical utility.

Since there is a significant learning curve to taking a visual field test, the first test should be regarded with suspicion, even if the reliability indices are good. Typically, two consecutive, reliable, and consistent tests are needed to establish a baseline.

The Pattern Standard Deviation (PSD) global index is considered one of the most important indices in the diagnosis of glaucoma. A repeatable PSD of 5% statistical significance is suggestive of glaucoma. However, other pathologies may also affect the PSD.

Early glaucomatous visual field defects typically present as nasal steps, paracentral scotomas, arcuate bundle scotomas. The presence of one or more of these suggests glaucoma. If repeatable, a group of three or more adjacent points showing statistically significant reductions in sensitivity with at least one point reaching the p < 1% significance level should be considered suspicious. If all points are on the same side of the horizontal meridian, one should consider this indicative of glaucomatous damage.

The Mean Deviation (MD) global index is a comparison of the deviation of a particular patient from age matched norms. It can be affected by uncorrected refractive error, pupil size, and media opacities and is not specific nor sensitive for glaucoma. A change of 2 dB per year is likely pathologic.¹⁷

The Glaucoma Hemifield Test (GHT), which is given on most visual field print outs, analyzes the superior and inferior hemifields and compares for statistically significant differences between them. This is significant as glaucomatous defects typically present asymmetrically with regards to these two hemifields. Two consecutive GHT “Outside Normal Limits” alerts are suggestive of glaucoma.

The role of optical coherence tomography in open-angle glaucoma

Spectral Domain Optical Coherence Tomography (SD-OCT) measures the differences in light reflectivity of different tissue layers.

These differences in light reflectivity allow the instrument to segment and measure these layers. By calculating the distance between the ILM and the posterior RNFL border the instrument can quantify the thickness of the RNFL. While visual fields are poor detectors of early glaucomatous changes and better of late ones, the reverse is true of OCT. It is better at detecting early changes and worse at detecting late ones. Of course, comparing VF defects with OCT defects and finding agreement strongly suggests glaucoma.

Many instruments will compare some values to a normative database. Each manufacturer has its own unique database and each instrument utilizes different methods of measuring and calculating. Thus when comparing results from different instruments, do so with caution.

The most commonly used OCT parameters to examine when attempting to distinguish between normal and early glaucoma have been shown to be:

Global/Average RNFL thickness
TSNIT asymmetries
Inferior quadrant RNFL thickness

Superior quadrant RNFL thicknessSpecial attention should be paid to the global/average RNFL thickness as it has a very high accuracy and reproducibility for detecting glaucomatous changes. A change of more than 5 µm on global/average RNFL thickness is suspicious for glaucoma.

Any changes detected should be confirmed with a subsequent confirmatory test as false positive can occur.¹⁹ Many instruments will also report vertical and horizontal C/D ratio, cup volume, RNFL symmetry, and disc area.

Most OCTs also have the ability to measure the ganglion cells withing the macula. Multiple studies have concluded that the ability to distinguish between normal eyes and glaucomatous eyes via macular ganglion cell measurements is high and comparable to other SD-OCT studies. Ganglion cell measurements are unique to the specific OCT but can be evaluated with proprietary normative database and progression analyses.^20,21

Though RNFL OCT measurements have been found to reach a floor effect before advanced glaucoma, ganglion cell measurements have a lower floor effect, allowing for valid OCT measurements of the ganglion cells into the advanced stages of glaucoma. (ref Bowd, Christopher, et al. "Estimating optical coherence tomography structural measurement floors to improve detection of progression in advanced glaucoma." American journal of ophthalmology 175 (2017): 37-44.)

Other tests to detect primary open-angle glaucoma

Electrodiagnositcs and corneal hysteresis (CH) are newer technologies that are becoming more commonplace in the diagnosis of glaucoma

Diopsys has a pattern ERG and VEP instrument available to clinicians called the Neuro Optic Vision Assessment System (NOVA). One study indicates that pattern ERG can detect early glaucomatous changes as much as eight years earlier than OCT. Another study found that VEP can detect functional loss in patients with structural deficits but normal visual fields.^21,22

Hysteresis is the energy lost to dissipation when stress is applied to a viscoelastic material, such as the cornea. CH is determined by measuring the difference in pressure at which an airjet causes the cornea to deform inward and the pressure at which it returns to normal.

Reichert’s Ocular Response Analyzer (ORA) combines noncontact tonometry with CH and calculates a corneal compensated IOP (IOPcc). IOPcc is an IOP measurement that compensates for the variable biomechanical properties of the cornea, providing a “truer” measurement of IOP.

CH is a measure of the viscoelastic properties of the cornea which is theorized to correlate to biomechanical properties of the lamina cribrosa and optic nerve head. CH has been found to be a strong independent risk factor for progression of glaucoma.^23-25

Primary open-angle glaucoma is a complex disease that is often difficult to diagnose. Considering the patient’s risk factors, IOP, ocular anatomy, and advanced diagnostic testing results in a systematic way will greatly aid in the diagnosis.

One important point to remember is that glaucoma is progressive.

Diagnosis of POAG suspect and initiating additional testing should have a low threshold given that the additional testing is non-invasive. One of the key deciding factors when trying to differentiate between POAG suspect and POAG is if there is any worsening of the structure or function of the optic nerve. Keep this in mind and diagnosing POAG will hopefully be a bit less difficult.

References

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