Although intraocular pressure (IOP) lowering is still the only proven way to treat glaucoma and reduce the risk of vision loss, recent research regarding the traditional risk factors that have been described in the large prospective clinical trials has expanded and enhanced our knowledge, allowing us to assess patients more thoroughly in earlier stages and to change the course of the disease. Individual risk assessment for glaucoma development and progression is essential to guide management decisions. Glaucoma is a complex disease with a very wide spectrum of severity that ranges from glaucoma suspects, who have normal optic nerves and visual fields but possess risk factors, to patients with terminal glaucoma and perimetric blindness. The benefit of identifying the patients with a higher risk profile is that we can be more aggressive in their treatment and follow up and halt or minimize vision loss before it occurs.

Age

It is irrefutable that increasing age, along with high IOP, is the strongest risk factor for onset and progression of glaucoma.^1-5 Although age increases risk among all ethnic groups, a recent review revealed it is highest in Hispanics (2.3 times greater risk per decade), followed by white populations (2 times greater risk per decade), South Asians (1.7 times greater risk per decade), black populations and Southeast Asians (1.6 greater risk per decade), and finally by East Asians (1.5 times greater risk per decade).⁶ Also, increased incidence of visual field (VF) deterioration occurs with older age (increased risk of visual field loss by 40% every 10 years).⁷ Although age is a nonmodifiable risk factor, it should always be taken into account when assessing risk of progression along with life expectancy.

Severity

Visual field testing is not only a fundamental examination for the diagnosis and follow-up of glaucoma, it can also constitute a tool for risk profiling. Visual field severity stage at the time of diagnosis has been hypothesized in many studies to be a risk factor for progression in glaucoma, where worse baseline VF damage is associated with faster progression and more severe disease,^8-10 but some studies have not shown a significant association between baseline VF damage and progression.^11,12

Recently, Liebmann et al analyzed whether VF damage at baseline measured in a linear scale (1/Lambert), which is better correlated with structural loss,¹³ was a risk factor for glaucoma progression if the slopes were also measured in 1/Lamberts per year. The results were very interesting, showing that when measured in a linear scale, eyes with mild VF damage lost more linear sensitivity than those with more severe damage, and that in a logarithmic scale (dB), worse baseline VF are associated with faster progression. This can help us understand that if we use a logarithmic scale (dB) the rate of progression will be underestimated in early stages and overestimated in more severe stages. A very important clinical application is that patients with early stage glaucoma should have a slower target of progression in dB/year than patients with more severe glaucoma, because they require a significant progression before it is shown in currently available functional testing methods.

Central VF testing in glaucoma has regained a very important place in the evaluation of the disease. Many recent studies have provided strong evidence supporting that central disease is linked to greater morbidity and disability, and that the structural and functional evaluation of the central vision is necessary in every stage of glaucoma to adequately stage and treat the disease. Garg et al considered whether the presence of baseline 24-2 central VF damage is predictive of global progressive VF loss. They followed 827 eyes prospectively and concluded that baseline central VF damage should be stratified as high risk because it is significantly associated with more rapid and significant global VF progression; in the study, patients with baseline central VF defects have a 3-fold likelihood of experiencing MD loss >5dB when compared to patients without central damage at baseline.¹⁴

Vascular Factors

Several clinical trials have reported blood flow reduction, impaired vascular autoregulation, and dysfunctional neurovascular coupling as contributing factors to glaucoma pathogenesis. This vascular theory of glaucoma damage has been supported by evidence showing that systemic hypotension, nocturnal blood pressure (BP) dipping, and low ocular perfusion pressure are associated with rapid progression of the disease.^15-17 Strangely, conditions related to decreased ocular perfusion pressure such as diabetes, cardiovascular disease, vasospasm, and antihypertensive medications have not been proven to relate to progression.^18-25

Recently, Chan et al studied the intraocular and systemic risk factors of a group of rapid glaucoma disease progressors and nonrapid disease progressors. Among the findings of the study, rapid progressors had lower central corneal thickness (CCT), had lower baseline IOP, were more likely to have disc hemorrhage (DH), and had higher prevalence of cardiovascular disease (CVD) and hypotension. It is very interesting that one of the findings was that CVD is an important factor for glaucoma disease progression, doubling the risk; also, patients with CVD who were rapid progressors had significantly lower baseline IOPs.⁸ A similar finding on CVD and glaucoma on the Early Manifest Glaucoma Trial (EMGT) reported patients having a hazard ratio (HR) of 2.75 for glaucoma disease progression, but this group of patients also showed a higher baseline IOP contrary to the group in this study.²⁶ This could imply that CVD is a risk factor for glaucoma progression independent of IOP.

Disc Hemorrhage

Disc hemorrhages have been associated with progression of glaucoma, especially in patients who are at or below “target,” normal, or low IOPs.^27,28 It is not clear if DH are the consequence of optic disc injury or if they are the primary event that makes the optic disc more susceptible to damage. Recently, Chou et al sought to identify the origin of DH by profiling hemorrhages from retinal vein occlusions (venous source of bleeding) and macroanuerysms (arterial source of bleeding) and comparing them to DH. They concluded that the densitometry profile of DHs indicates that they have arterial origin, supporting a theory that treatments targeting autoregulation (with brimonidine or other agents) could likely reduce progression.²⁹

Another recent study regarding DH conducted in Korea by Lee et al concluded that thinning of the ganglion cell-inner plexiform layer (GCIPL) thickness measured by optical coherence tomography (OCT) was significantly faster in glaucomatous eyes with DH that in eyes without them,³⁰ reaffirming that DHs are a strong indicator of glaucoma structural progression and that central (macular) evaluation of glaucoma is important in early stages of the disease and a useful tool when assessing progression.

CSF Pressure

It has been long theorized that low intracranial pressure (ICP) causes an increased translamina cribrosa pressure difference (TLCPD), thus causing glaucoma and progression of the disease in patients with normal IOP. The TLCPD has been defined as IOP minus ICP, and the resulting difference is what causes a pressure gradient effect that creates a similar mechanical condition to an elevated IOP at the lamina cribrosa (LC).³¹

Recently, this hypothesis was tested by Wang et al, who investigated the effects of IOP and ICP on the LC in vivo on rhesus monkeys.³² The researchers manipulated the IOP and ICP while imaging the LC with OCT in multiple IOP/ICP combinations and measured different structural features, such as the LC thickness and the characteristics of its collagenous beams and pores; afterwards the LC was removed and histologically studied to confirm the findings. This study helps validate previous evidence that had been presented in ex-vivo and epidemiological studies that ICP changes have important effects on the LC, and although more research is needed to reach more categorical conclusions, it strongly guides us to consider ICP when assessing a patient with glaucoma.

In another perspective, Linden et al state that the evidence that supports this theory has assessed IOP in an upright position and ICP in a horizontal position, so the pressure difference has not truly been evaluated. They conducted the only prospective study that has tested ICP and IOP in supine and upright positions and their results contradict all previous research, because they did not find that people with normal tension glaucoma (NTG) have low ICP.³³ The study was limited, however, by a low sample size and by several confounding variables between normal tension and control subjects.

The relationship between ICP and glaucoma, in particular NTG, is an interesting hypothesis that has been the subject of a fair amount of research, but results have been somewhat controversial. Evidence points to TLCPD, secondary to low retrolaminar pressure as a potentially strong risk factor for glaucoma and its progression,^34-36 but more investigation that overcomes the limitations of previous research is needed for more conclusive data applicable to clinical practice.

Corneal Thickness

There has been compelling evidence that central corneal thickness (CCT) is an integral part of the evaluation of a patient with ocular hypertension and glaucoma, especially regarding risk stratification. It has been proven to be a strong a risk factor for the onset of glaucoma. A thin CCT (<555 microns) was identified as a strong predictive factor for development of primary open angle glaucoma (POAG) in patients with ocular hypertension in The Ocular Hypertension Study (OHTS);³⁷ this finding was supported by the European Glaucoma Prevention Study (EGPS)³⁸ and has been confirmed in subsequent research. A thin CCT has also been proposed as a risk factor for progression, and has been found to be more prevalent among patients with more severe glaucomatous damage.^25,39,40

There are many hypotheses about the relationship between CCT and glaucoma damage. We know that IOP measurement is affected by CCT, where thin corneas underestimate IOP and vice versa.⁴¹ Also, being that cornea, sclera, and optic disk may be seen a continuous structure, a thin CCT could reflect the deformability and frailty of the lamina cribrosa and posterior sclera; although this has been contradicted in other studies.^42-44 Another theory is that a thin cornea could allow more oxygen into the anterior chamber, leading to oxidative damage of the angle and ocular hypertension.⁴⁵ To this day, the hypotheses have not been proven by research.

A recent retrospective case-control study led by Batawi where 116 patients with and without OAG had their central corneal epithelial, stromal, and total thickness measured concluded that patients with glaucoma have lower stromal corneal thickness and lower total corneal thickness, and that the use of glaucoma medications leads to lower corneal thickness measurements. They also found an association between a thinner CCT and more severe disease.⁴⁶ This is the first study that segments corneal thickness, and it confirms previous findings regarding the association between CCT and glaucomatous damage.

Corneal Hysteresis

Corneal hysteresis (CH) is a dynamic biomechanical property of the cornea that measures the ability of the cornea to resist deformation. CH is lower in eyes with glaucoma when compared to normal eyes. Low CH has also been associated with structural and functional progression of glaucoma, and it is associated with better IOP reduction following hypotensive treatment.⁴⁷

Recent prospective studies suggest that low CH is not only a strong risk factor for glaucoma progression, but that it appears to be a more appropriate parameter than CCT because it describes corneal physical and biomechanical properties better.^48,49 Corneal hysteresis correlates with biomechanical properties of posterior sclera al lamina cribrosa, so an eye with low CH is less capable of resisting IOP strain and therefore more prone to glaucomatous damage.^50,51

Zhang et al published a prospective study that followed 133 patients with glaucoma to investigate the relationship between baseline CH, CCT, IOP, and rates of retinal nerve fiber layer (RNFL) loss. They concluded that CH is significantly associated with faster rates of RNFL loss, even after adjusting for other factors that affect rate or progression; they esteem that every 1 mmHg lower CH can be associated to 0.13 microns per year faster rates of RNFL loss. The authors conclude that CH is of greater value than CCT for determining progression.⁵² This complements previous findings by Medeiros et al in a prospective study that found that lower CH has a significant effect on VF progression, where every 1 mmHg lower CH was associated with a 0.25%/year faster visual field index decline,⁴⁹ confirming that both structural and functional progression are seen in lower CH measurements.

More recently, Susanna et al published a prospective study to investigate the role of CH as a risk factor for the development of glaucoma. They followed 287 glaucoma suspects who had their CH measured at baseline. At the end of the study, 19% of the eyes developed glaucoma; baseline CH in these patients was significantly lower than in patients who did not develop the disease. Every 1 mmHg lower CH at baseline was associated with a 21% increase of developing glaucoma; even after adjusting for age, IOP, CCT, Pattern Standard Deviation (PSD) and treatment CH was still a strong predictor for the onset of the disease.⁵³

Of all the risk factors regarding glaucoma onset and progression, CH is the one that has developed the most compelling and new evidence over the last years. There is enough proof to say that CH is a valuable tool to include in the risk assessment of glaucoma patients, helping to identify high risk patients and helping the physician make management choices.

Conclusion

Glaucoma is a potentially devastating and disabling disease. The number of tools to identify and treat glaucoma at an earlier stage is increasing, changing the course of the disease by individualizing management and providing more effective therapy. One of the most important aspects of managing a patient with glaucoma is recognizing if we are facing a high-risk patient who requires special considerations during management; today we have more information than ever to profile our patients and stop visual loss from glaucoma. GP

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Nathan M. Radcliffe, MD, is a clinical assistant professor in the department of ophthalmology at the New York Eye and Ear Infirmary and a surgeon at the New York Eye Surgery Center. Dr. Radcliffe reports no related disclosures. Reach him at drradcliffe@gmail.com.

Daniela Alvarez-Ascencio, MD, is a second-year glaucoma fellow at the Association to Prevent Blindness (APEC) in Mexico City, Mexico. She reports no related disclosures. Reach her at alvarezdann@gmail.com.