Preface

This book provides useful information to physicians who manage patients with ocular hypertension. It answers questions such as, is ocular hypertension an actual disease? How it is possible to detect it? How does this condition force people to modify their lifestyles? Because the optic nerve damage due to ocular hypertension is one of the most important causes of irreversible vision loss, it is essential to manage this condition in the best way possible. The book examines advances in technology that allow for earlier diagnosis and better management of patients, but physicians must be aware of the limits and challenges of new devices recently introduced. Finally, this volume helps physicians improve their abilities to manage ocular hypertension and its connections with other ocular and systemic diseases.

> **Michele Lanza** University of Campania "Luigi Vanvitelli", Italy

Section 1 Ocular Hypertension

## **Chapter 1** Ocular Hypertension in Blacks

*Daniel Laroche and Kara Rickford*

## **Abstract**

Ocular hypertension occurs when intraocular pressure (IOP) is greater than the normal range with no evidence of vision loss or damage to the optic nerve. Individuals with ocular hypertension have an increased risk for glaucoma. The mean normal IOP is 15 mmHg and the mean IOP of untreated glaucoma is 18 mmHg. Elevated IOP commonly occurs in patients over the age of 50 and is often due to enlargement of the lens, narrowing of the angle, iridolenticular apposition, and pigment liberation that obstructs the trabecular meshwork. Cataract surgery and lensectomy can lower IOP and reduce the risk of glaucoma. The global wealth inequality of Blacks has created health inequities that have led to decreased access to surgical care contributing to higher rates of blindness from glaucoma. Greater education on the benefits of early cataract surgery and trabecular bypass for higher risk patients, as well as addressing wealth and health inequities, can help to bend the curve of blindness from glaucoma.

**Keywords:** ocular hypertension, glaucoma, Blacks, cataract surgery, trabecular bypass, African-American

## **1. Introduction**

Ocular hypertension occurs when the pressure in the eye (intraocular pressure or IOP) is beyond the normal value with no signs of vision loss or damage to the optic nerve [1]. With ocular hypertension, the aqueous humor (fluid produced by the eye) is poorly drained. The buildup of fluid in the eye leads to an increase in IOP that could potentially lead to damage of the optic nerve, causing glaucoma [2]. The mean normal IOP is 15 mmHg and the mean IOP of untreated glaucoma is 18 mm Hg [1]. Ocular hypertension typically presents with no signs or symptoms, making it difficult to detect without access to an eye exam. Individuals with elevated IOP may be treated with cataract surgery and lensectomy [2, 3]. To properly address populations at risk for ocular hypertension, it is advantageous to determine how demographic variables may impact an individual's susceptibility to blindness. Demographic variables are innate or non-changeable determinants of a disease. Addressing inequities in wealth, health, and access to medical care, as well as improved education on the benefits of early surgical intervention, can bend the curve of blindness from glaucoma. In this chapter, we use epidemiologic studies focusing specifically on Blacks to describe the prevalence and management of ocular hypertension.

## **2. Prevalence of ocular hypertension in blacks**

In 2019, Black Americans made up 12.8% of US population, accounting for over 42 million people [4]. Although Blacks make up a minority of the population, many eye diseases, including ocular hypertension and glaucoma, affect a disproportionate number of Blacks, leading to higher rates of vision loss than documented in white-Americans [5]. Definitions of race and ethnicity have been ill-defined in past medical literature, with many overlaps. Therefore, the term "Blacks" in this context refers to an individual of black African descent. The population of Blacks in the Caribbean is over 21 million and in Africa is close to one billion [6]. There are also issues of decreased access to surgery in both locations [7].

While it has been universally accepted and documented that Blacks have higher prevalence of ocular hypertension, the degree of prevalence may differ for varying black populations. For example, the black-American and black-Caribbean populations studied in the Baltimore Eye Survey and the Barbados Eye Study, respectively, are ethnically unique. Both populations of Blacks presented with a high prevalence of ocular hypertension, but to a different degree. The prevalence of ocular hypertension in the black-Caribbean population was reported at levels nearly twice that of the black-American population [8–11]. Studies have also reported a notably higher prevalence of ocular hypertension in Blacks in comparison to other racial groups (primarily white) [12, 13].

In response to a lack of substantial ocular research with Black study participants, extensive population-based studies including the Baltimore Eye Survey [9], The Ocular Hypertension Treatment Study [2], The Barbados Eye Study [8], and the African American Eye Disease Study [13] were created to address the disproportionate prevalence of eye diseases present in Blacks. Further studies are needed to continue to build upon this body of research, particularly to look at earlier interventions of cataract surgery and trabecular bypass as an earlier intervention to prevent glaucoma.

## **3. Mechanism of ocular hypertension in blacks**

Studies have shown that with age the crystalline lens increases in width. During accommodation, the iris bows posteriorly. With age there is increased contact between the posterior iris pigment epithelium and lens zonules leading to pigment liberation and obstruction of the trabecular meshwork [14]. This is often seen with heavier pigment in the trabecular meshwork inferiorly compared to superiorly on gonioscopy [15]. The increased width of the lens can also lead to pupillary block and iris obstruction of the trabecular meshwork leading to elevated intraocular pressure. This common mechanism of ocular hypertension in persons over the age of 50 is often overlooked by physicians. Current physicians and those in training must be better educated to look for this clinically and intervene promptly. Early cataract surgery and lensectomy is beneficial to remove the large lens and trabecular bypass to restore aqueous outflow via the obstructed trabecular meshwork [14].

### **4. Genetic influence on ocular hypertension**

Previous studies have shown intraocular pressure (IOP) to be highly heritable, indicating possible genetic influence on the development of ocular hypertension [12, 16]. There is additional substantial evidence suggesting that ocular hypertension leading to glaucoma may have a genetic component [17], but the specific genetic risk factors have not yet been identified. A 2012 genome wide association study conducted in 11,972 participants from The Netherlands, UK, Australia, and Canada investigated candidate genes in human ocular tissue to identify susceptibility to elevated IOP and glaucoma [12]. Elevated IOP commonly occurs in patients

#### *Ocular Hypertension in Blacks DOI: http://dx.doi.org/10.5772/intechopen.96606*

over the age of 50 and often presents with enlargement of the lens, narrowing of the angle, iridolenticular apposition, or pigment liberation that obstructs the trabecular meshwork. Genes regulating these ocular components were studied and the results revealed that genetic variants expressed in genes GAS7 and TMCO1 were associated with changes in IOP in the populations studied. Both revealed only marginal evidence for ocular hypertension, as GAS7 was associated with a 0.19 mmHg decrease in IOP and TMCO1 was associated with a 0.28 mmHg increase in IOP [12]. Additional findings revealed that individuals of European ancestry expressed the GAS7 variant at 0.44 frequency while those of African ancestry expressed the same variant at 0.12 frequency [12]. The lower frequency of this variant in Blacks may reflect the elevated IOP common in individuals of African descent and requires further research.

While impressive strives have been made over the past two decades to identify genetic components of ocular diseases [18], a comprehensive understanding of the pathophysiology has frequently been limited to individuals of European and Asian ancestry, requiring an increased need for genetic research in Blacks and other understudied populations. For example, multiple genetic variants in genes associated with elevated IOP were discovered in non-Black populations and a majority do not replicate, nor have an effect, in Blacks [19–21]. In response to an increased need for the identification of genetic risk factors that underlie elevated IOP in the understudied population of Blacks, the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study was created in 2014 and took place over the course of five years to address these research disparities [22]. This study identified a genetic variation known as a single nucleotide polymorphism (SNP) involved in the homeostasis of the trabecular meshwork [23]. The trabecular meshwork (TM) is located in the anterior portion of the eye and regulates the outflow of the aqueous humor into circulation [24]. If resistance increases in the TM during aqueous humor outflow, intraocular pressure may rise leading to ocular hypertension. By identifying a genetic variant that may affect the TM in Blacks, the POAAGG study has made a pertinent finding to our understanding of the role of genetics in ocular hypertension and glaucoma. As one of the first large cohort studies with over 5,000 study participants, additional analyses are needed to further validate the implications of this study.

In addition, the progression of elevated IOP in Blacks leading to ocular hypertension is likely a combination of genetic, environmental, aging and socioeconomic factors, as well as others not mentioned. These demographic variables will continue to be explored throughout this chapter.

## **4.1 Central corneal thickness in ocular hypertension**

Intraocular pressure is routinely measured in clinical practice to assess various conditions within the eye, including that of the optic nerve and visual field [25]. Goldmann applanation tonometry is the most common technique used to measure IOP, but its accuracy and use as a diagnostic tool may be impeded by the rigidity of the cornea [25]. A thicker cornea may cause an overestimate of IOP and a thinner cornea may cause an underestimate of IOP. The consensus on the necessity to correct IOP based on central corneal thickness is not yet clear. While CCT is statistically significant as a predictor of glaucoma development [2], it does not present as an independent risk factor [26].

The Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) recognized central corneal thickness as one of the most significant predictors for primary open-angle glaucoma [2, 27]. The mean central corneal thickness is about 560 μ m and the risk for developing ocular hypertension

has been reported to nearly double (hazard ratio of 1.82) for every 40 μm decrease [28]. Patients with thin corneas (<555 μm) [2] may present with an underestimated IOP reading, placing the individual at potential risk if actual IOP is elevated. The primary diagnostic criteria for ocular hypertension is IOP, so any factor that hinders this measurement may lead to an errant diagnosis. Patients with ocular hypertension typically present with thicker corneas, which may lead to an overestimation of IOP, while primary open angle glaucoma patients present with thinner corneas [29]. While the influence of elevated IOP on central corneal thickness has not yet been determined, individuals whose IOPs have been reduced pharmacologically by at least 20% demonstrated no change in corneal thickness [30].

Differences in central corneal thickness were noted between black Americans and white Americans. In the OHTS, Blacks were found to have thinner central corneal thickness (555.7 μm), resulting in lower applanation readings and a miscalculated estimation of the true level of IOP [30]. The South African Eye Study [31] also measured differences in central corneal thickness and compared the findings to measurements of intraocular pressure in Blacks, mixed ethnicity peoples, and whites. The findings revealed that Blacks had the thinnest corneas and highest IOP, followed by mixed ethnicity then white individuals.

These results suggest the possible need for refining the risk factor definitions when measuring central corneal thickness and IOP in varying populations. While obtaining a central corneal thickness measurements for all patients may not be necessary, patients with ocular hypertension should continue to be monitored to measure accurate IOP and determine possible susceptibility to glaucoma.

## **4.2 Morphological changes in the retinal nerve fiber layer in ocular hypertension**

Differing from glaucoma, ocular hypertension presents with a normal optic nerve and no signs of damage. Ocular hypertension is often a precursor to glaucoma as abnormally high pressures in the eye may lead to damage of the optic nerve causing vision loss or blindness [1]. Studies have indicated differences in the structure of the optic nerve between Blacks and whites [32–33]. The optic disc area was 12% larger in Blacks compared to Whites [32]. The larger optic nerve may cause a greater strain at similar pressure levels, but it is not clear if larger optic discs affect one's susceptibility to ocular hypertension as there are incongruous reports [10, 34]. The impact of these differences has been postulated to affect the increased susceptibility of Blacks to ocular hypertension and glaucoma.

The retinal nerve fiber layer (RNFL) is primarily comprised of retinal ganglion cell axons that progressively diminish in glaucoma. As a result, the RNFL thins considerably and may present as an early manifestation of glaucoma [35]. As a precursor to glaucoma, RNFL was measured in patients with ocular hypertension and the results revealed a significant thinning of RNFL of about 15% in ocular hypertensive eyes as compared to normal eyes [36]. Other studies have yet to demonstrate significant differences RNFL between normal eyes and those with ocular hypertension, possibly due to the sensitivity of the instruments used to measure and the study population [36, 37].

### **5. Inequities contributing to ocular hypertension in blacks**

Vision loss is a pertinent public health challenge that requires the efforts of many to overcome [38, 39]. Addressing these disparities involves contending with the

#### *Ocular Hypertension in Blacks DOI: http://dx.doi.org/10.5772/intechopen.96606*

pervasive economic and racial inequalities that have had a disproportionate impact on Blacks, particularly in healthcare utilization. These inequities are evident in a 2020 study documenting the recency of eye examinations among black adults over the age of 55 [40]. In this study, 13.4% of participants (n = 740) reported having no eye examination in the last five years and nearly 25% had not had an eye exam in the last year [40]. Concerningly, 20% of study participants with diabetes mellitus were not instructed by other healthcare providers to seek annual eye examinations.

## **5.1 Health and wealth inequities in blacks**

Systemic and social inequities have resulted in poor health outcomes in Blacks [41]. When examining wealth in the United States, there is countless evidence of extensive racial disparities. In 2016, the net worth of the average white family in the US was nearly ten times more than that of a Black family at \$171,000 and \$17,150 respectively [42]. These extensive differences in wealth and income reflect the consequences of years of discrimination, segregation, and inequality that mark the history of the US from its inception. The wealth gap between Blacks and whites in the US demonstrates the differences in opportunity afforded to citizens [42]. Colonialism has contributed to similar wealth disparities in the Caribbean and Africa. Differing from the circumstances in developing countries, the eye health care system in the United States is highly capable of delivering the care necessary to treat patients [41, 43]. However, much improvement is needed in the means by which education is delivered to the public and effective screening may take place.

The history of medicine and health care in the United States is tainted by a myriad of forms of injustice and violence towards Blacks that includes segregation of medical facilities, unequal healthcare access, and disdainful medical experimentation [44, 45]. Today, these inequalities are especially evident in employment, housing, and wealth opportunities in medically underserved areas and populations (MUA/P) [46–48]. MUA/P have been defined by the Health Resources and Services Administration as areas or populations having too few health care providers, high poverty or high elderly populations [49]. In addition, there are also social factors that have had strong implications on the health outcomes of Blacks, particularly poverty, food insecurity, and affordable housing. Low-socioeconomic status and race have been independently associated with increased vision loss placing poor Blacks at an increased risk [47]. These social factors that have often led to poor health outcomes in Blacks are rooted in racism and implicit biases that have to be recognized and changed at the personal, medical, and institutional level in order to lead to change [50].

Many studies have reported the association between visual impairment and poor quality of life, as well as physical and mental illness [51–53]. Unilateral and bilateral vision loss and blindness can impact a person's quality of life by affecting their ability to read, walk, commute, and carry out daily activities [54]. In addition to the disparities previously mentioned, blindness can exasperate the inequities faced by Blacks in the US. Early treatment of ocular hypertension by reducing elevated IOP by 20% can reduce the risk of developing glaucoma in half [2], thereby reducing the risk of blindness. Earlier cataract surgery, clear lensectomy, and trabecular bypass may reduce it even more. Implementing measures to address ocular hypertension in Blacks can help reduce the risk of blindness and address health inequities in the medical community. In addition, public policy is needed to develop models of healthcare that make services more accessible, particularly in communities that are medically underserved.

#### **5.2 Insurance and access to care**

Access to health care can impact one's health outcomes. The utilization of healthcare may be determined by whether people know care is needed, whether obtaining care is wanted, and whether care can be accessed [55]. Access is often used to describe the ease of obtaining care, including its availability, the accommodations provided, and affordability. Health care in the United States often cannot be utilized without insurance, regardless of the presence of a healthcare provider that is geographically accessible. The public health challenge regarding ocular hypertension is that if the elevated IOP was detected earlier on, further exasperation of the condition could be slowed and potential diseases could be prevented [56, 57]. With newer surgical approaches progression can be halted with earlier cataract surgery/ clear lensectomy and trabecular bypass.

Successful treatments for elevated IOP have included topical medications, surgery, or laser [58]. Reducing IOP significantly may lead to a delay in progression to optic nerve damage, visual field loss, or glaucoma [59]. Several studies have reported the impact of lack of medical care on health outcomes [60, 61]. The Salisbury Eye Evaluation Study [62] was a population-based study that sought to investigate the causes of blindness and visual impairments of adults between the ages of 65 and 84. The study revealed higher levels of blindness and visual impairments in Blacks compared to whites, with 37% of the conditions classified as surgically treatable and 44% categorized as targets for low vision remediation. The study was not able to identify patients whose eye condition was amenable and chose not to undergo surgery for reasons including financial barriers, fear of the surgical procedure, or absence of functional loss. It is important to encourage all patients, particularly those with ocular hypertension, to seek continuous to monitor their condition.

The Affordable Care Act (ACA) was enacted in March 2010 with its primary goals being to make affordable health insurance available to more people and to generally lower the cost of health care [63]. Better health outcomes in Blacks have been linked to increases in health insurance coverage under the ACA [64]. While uninsured rates were reduced, Black Americans remained 1.5 times more likely to be uninsured than non-Hispanic white Americans [65]. Additionally, data gained from the National Health Interview Survey conducted between 2014–2016 revealed that access and utilization of eye care is lower among racial and ethnic minorities [66]. Increased access to health care and affordable insurance may improve the health outcomes of vulnerable populations with ocular hypertension.

## **6. Patient education for ocular hypertension**

Patient education is an interactive process in which learning may take place between the healthcare provider and the patient. Increased patient education of vision health may lead to an increasing trend of eye doctor visits. Previous studies have reported that those with more education are more likely to seek care from an eye care professional as opposed to those with less education [67]. As a result of ocular hypertension, many Black patients were reported to present to an ophthalmologist with more extensive damage to the optic nerve as compared to whites [68]. As a result, the disease progression in Blacks was more vulnerable to malignancy even after intervention is initiated. Safer earlier cataract surgery and trabecular bypass are important treatment options that should be offered earlier.

Educating patients on ocular hypertension involves sharing the risk factors associated with the eye condition such as family history, age, medical conditions, and

#### *Ocular Hypertension in Blacks DOI: http://dx.doi.org/10.5772/intechopen.96606*

past eye injuries, as well prevention and treatment options. Due to the asymptomatic presentation of ocular hypertension with no signs of vision loss, it is possible that patients have not/will not seek treatment until further damage and vision loss occur. Prior recorded interactions between physicians and patients have found that providers were less likely to educate Black patients about glaucoma and were also less likely to educate patients of lower health literacy about glaucoma medications [69]. It is important for the patient's eye health that ocular hypertension and its potential progression to glaucoma are described and apprehensible, particularly to those in populations most at risk. Through patient education of ocular hypertension, the patient may better understand their susceptibility to eye disease and can seek early treatment if necessary.

## **7. Prevention and implementation of changes to address ocular hypertension in blacks**

Given the information presented in this chapter, initiation of treatment for ocular hypertension may be started earlier in Blacks with the possibility of arresting or reducing elevated IOP. The aging population of adults aged 65 and older is continuously increasing with expectation of this number to reach nearly 90 million in the US by 2050 [70]. In addition, growing levels of obesity increasing the prevalence of diabetes make an increasing number of individuals at risk for vision loss in the future. As the risk factors for ocular hypertension increase, recognition of patient vulnerabilities and systemic level changes are needed to ensure that the needs of patients are properly and conveniently addressed.

## **8. Conclusion**

This chapter has demonstrated the unique demographic and ocular characteristics that have affected Blacks in the progression of ocular hypertension. The combination of race, socioeconomic status, and access to treatment may influence the diagnosis and health outcome of individuals with ocular hypertension. Acknowledging these factors and implementing changes to promote early diagnosis and treatment, as well as addressing health and wealth disparities in high-risk populations, can lead to lower rates of glaucoma and blindness. Physician advice through patient education, as well as affordability, continuity, and frequent access to care has demonstrated a strong association with increased eye care services [71]. Diagnosis and early intervention of elevated levels of intraocular pressure and ocular hypertension may reduce the risk of glaucoma, vision loss, and blindness in future patients.

## **Conflict of interest**

The authors declare no conflict of interest.

*Ocular Hypertension - The Knowns and Unknowns*

## **Author details**

Daniel Laroche1 \* and Kara Rickford<sup>2</sup>

1 New York Eye and Ear Infirmary, Icahn School of Medicine of Mount Sinai, New York, NY, USA

2 School of Medicine, New York Medical College, Valhalla, NY, USA

\*Address all correspondence to: dlarochemd@aol.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 2**

## Retinal Vascular Implications of Ocular Hypertension

*Fidan Jmor and John C. Chen*

## **Abstract**

In this chapter, we review the basics of retinal vascular anatomy and discuss the physiologic process of retinal blood flow regulation. We then aim to explore the relationship between intraocular pressure and retinal circulation, taking into account factors that affect retinal hemodynamics. Specifically, we discuss the concepts of ocular perfusion pressure, baro-damage to the endothelium and transmural pressure in relation to the intraocular pressure. Finally, we demonstrate the inter-relationships of these factors and concepts in the pathogenesis of some retinal vascular conditions; more particularly, through examples of two common clinical pathologies of diabetic retinopathy and central retinal vein occlusion.

**Keywords:** retinal hemodynamics, baro-damage, ocular perfusion pressure, diabetic retinopathy, central retinal vein occlusion, blood flow

## **1. Introduction**

The retina shares similar anatomical features and physiological properties with other end organs such as the brain and the kidney, namely the presence of blood–brain, blood-kidney and blood-retina barrier as well as non-anastomotic end arteries [1]. Retinal fundoscopy and digital imaging have allowed for retinal microvascular abnormalities to be directly and non-invasively identified and studied as a means of better understanding the manifestation of systemic microcirculatory disorders.

Although not yet completely understood, hemodynamic factors such as perfusion pressure, blood viscosity, vascular resistance and the variations on vessel caliber that ensue, determine the blood supply and flow to the retina. By understanding these processes and their disturbances, we can better characterize the pathological processes that occur in many ocular and systemic diseases such as glaucoma, agerelated macular degeneration and diabetic retinopathy, to name a few.

Retinal hemodynamics are influenced by a number of factors. Blood flow, arterial and venous pressure, vascular resistance, and blood viscosity all play important roles. Our understanding of their inter-relationship is derived from concepts used in fluid flow systems borrowed from engineering and from other physiologic studies of blood flow. Mathematically, this relationship is often simplified into Poisseuille's equation, which we will discuss more in detail in the diabetic retinopathy section. However, it is important to know that Poisseuille's equation is used mainly for Newtonian fluid in a system with laminar flow. In the retinal arterioles, the flow is often turbulent; and blood itself is not truly a Newtonian fluid. In this chapter, we will not delve into the detailed discussions of mathematical modeling,

but will only use them to better understand the hemodynamics and its biologic consequences.

Clinical evidence for the relationship between intraocular pressure (IOP) and retinal hemodynamics remains inconsistent and difficult to interpret. The reasons are two-fold. Firstly, it is difficult to capture the data of multiple variables that may contribute to hemodynamics in a clinical setting. Second, in a complex system such as retinal circulation, many variables act as both dependent and as independent variables in many feed-back loops. Moreover, these feed-back loops may vary depending on the underlying disease processes in individuals with multiple co-morbidities [2, 3].

## **2. Blood supply to the posterior segment**

#### **2.1 Retinal blood supply**

The metabolic demands and the oxygen requirement of the retina are met by two distinct vascular systems. The inner two thirds of the retina is supplied by inherent intra-retinal vessels, fed by the central retinal artery, and drained via the central retinal vein. The photoreceptors and outer one third of the retina are supplied by the choroidal circulation [4]. Both of these supplies originate from the ophthalmic artery, which itself is a branch of the internal carotid artery.

The central retinal artery traverses through the orbital portion of the optic nerve, entering the optic disc through the lamina cribrosa. At the optic nerve, there is a combination of choroidal and retinal arterial circulation, details of which are dealt with in other chapters. The central retinal artery branches into four principal intra-retinal arteries. These further bifurcate into increasingly smaller arterioles, feeding eventually into a capillary bed as they extend towards the peripheral retina (**Figure 1**).

These capillary beds form interconnecting networks linking terminal branches of pre-capillary arterioles and post-capillary venules. Although in the juxta-papillary region this is arranged in three layers, the peri-macular region has two layers; a superficial layer located in the nerve fiber and ganglion cell layers and a second, deeper layer in the inner nuclear and outer plexiform layers. With the exception of a small avascular rim, both superficial and deep plexi reach almost to the edge of the human retina [6, 7]. The fovea is also avascular, receiving adequate oxygenation via the choroidal circulation [8].

#### **Figure 1.**

*(A) Sagittal drawing of the human eye showing the retinal and choroidal circulation of the left eye. (B) Crosssectional drawing of the retinal and choroidal vasculature at the level of the fovea. Adapted from Anand-Apte and Hollyfield with drawings by Dave Schumick [5].*

Post-capillary venules feed back into the superior and inferior hemi-central retinal veins, eventually uniting into the central retinal vein which centralizes at variable depths within the optic nerve eventually draining into the cavernous sinus.

The neighboring endothelial cells lining the retinal vasculature form tight junctions. Together with pericytes, they form a highly selective semi-permeable border that prevents solutes in the circulating blood from non-selectively crossing into the interstitial space within the neuroretina, constituting the inner blood retina barrier.

## **2.2 Choroidal blood supply**

The choroid has approximately 80% of the total ocular blood supply relative to iris-ciliary body and retina [9] and consists of three distinct layers of gradually decreasing vessel caliber; Haller's layer comprises the outer, larger sized vessels, Sattler's layer is intermedial with medium-sized vessels, and the deeper choriocapillaris contains vessels with the smallest diameter [10]. The anterior choroid is supplied by the long ciliary arteries, whereas the posterior choroid is supplied by the short posterior ciliary arteries. The entire choroid drains into the vortex veins [11].

Unlike the retinal vasculature, choroidal capillaries are fenestrated, allowing free passage and exchange of intravascular contents and interstitial space, including macromolecules and cellular components. It is the monolayer of retinal pigment epithelial cells, with tight junctions at the apical aspect, that form the outer bloodretinal barrier (**Figure 1**).

## **2.3 Blood supply to the optic nerve head**

The blood supply to the optic nerve head is complex, deriving from both the central retinal artery and from the choroid through the short posterior ciliary arteries. It has been specifically discussed in an earlier chapter in this book.

## **3. Blood flow within the posterior segment**

## **3.1 Retinal blood flow**

The human retina is a metabolically demanding tissue. Tissue damage and cell death can be brought about by small alterations in oxygenation or blood flow; hypoperfusion leads to hypoxia and ischemic damage; [12] whilst hyperperfusion and/or high oxygen tension leads to formation of reactive oxygen species, leading to oxidative damage [13]. Retinal blood flow must necessarily be highly regulated, and is dependent on the relationship between perfusion pressure and local resistance [11].

Under physiological conditions, retinal arterial pressure is more or less equal to mean arterial blood pressure and retinal venous pressure is more or less equal to the IOP. The difference between these pressures constitutes the driving force propelling blood through ocular capillary beds. In general, mean ocular perfusion pressure (MOPP) is positively correlated with arterial blood pressure and negatively correlated with IOP [14].

MOPP, defined as the difference between two-thirds of the mean arterial pressure (MAP) and the IOP, is a clinically modifiable factor in diseases such as Diabetic retinopathy (DR) where there is altered tissue perfusion. This will be reviewed in more detail later in the chapter.

The normal retinal hemodynamic response to increases in perfusion pressure is an increase in vascular resistance, [15] otherwise referred to as the myogenic

response. This behavior is intrinsic to smooth muscle cells such as those that line retinal arterioles and is independent of metabolic and hormonal influences.

#### **3.2 Choroidal blood flow**

Whilst retinal blood flow is characterized by a low perfusion rate, a high vascular resistance and a high oxygen extraction, the choroid, by contrast, shows a low vascular resistance, high perfusion rate and low oxygen extraction [11]

## **4. Regulation of blood flow in the posterior segment**

#### **4.1 Retinal blood flow regulation**

Ordinarily, blood flow is regulated in response to changes in perfusion pressure and tissue oxygen tension.

Retinal circulation differs from blood flow in other non-neural systems in that local neural activity can evoke localized changes in blood flow. This behavior, termed neurovascular coupling, has been observed in the retina [16, 17] and is an emerging area of research in glaucoma [18].

More importantly, the regulatory effect of perfusion pressure on blood flow is blunted through the process of autoregulation. That is, the retinal blood flow, like that of the blood flow in the brain, is maintained or stabilized through a wide range of variations of perfusion pressure. Previous studies have shown that retinal autoregulation is adequately compensated in experimental elevations of IOP up to 29 mmHg, [19] whilst the retinal vasculature behaves more passively for greater increases in IOP [20]. This autoregulatory response is also noted in incidences of increased perfusion pressure such as periods of dynamic and static exercise; where a rise in perfusion pressure of up to 34% rise results in a rise in flow of only 4–8% [21, 22]. Teleologically, autoregulation is a protective mechanism to maintain a steady blood flow to the retina

#### **Figure 2.**

*Schematic of blood flow autoregulation in the eye. When fluctuations in ocular prefusion pressure exceed the autoregulation range defined by this plateau, vasomotor adjustments are incomplete and blood flow changes passively as ocular perfusion pressure changes. Figure adapted with permission from Wareham and Calkins [18].*

#### *Retinal Vascular Implications of Ocular Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98310*

to satisfy its metabolic demands which changes very little as compared to the wide swings of systemic blood pressure and even diurnal variations of IOP.

The autoregulation curve (**Figure 2**) shows how blood flow changes in response to ocular perfusion pressure. The curve includes a plateau region across a range of ocular perfusion pressures where the blood flow is fully compensated by the above mentioned autoregulatory mechanisms.

### **4.2 Choroidal blood flow regulation**

Choroidal blood flow regulation is distinctly different from that of the retina; [23]. Firstly, the choroidal vascular bed is extensively innervated [24] though only partly autoregulated. There is little to no oncotic pressure gradient between intraand extravascular spaces within the choroid due to capillary fenestration. This lack of oncotic pressure coupled with the absence of lymphatic vessels, allows for the onset of choroidal effusion if the IOP drops below a certain level.

## **5. Effect of intraocular pressure on retinal hemodynamics**

The high metabolic and oxygen demand posed by retinal tissue is met by maintaining a steady blood flow. IOP is a major determinant of both retinal vascular perfusion pressure as well as vascular transmural pressure.

Over the past two decades, elegant mathematical modeling has been used to assess the effect of IOP elevation on the lamina cribrosa [25–27] and on arteriovenous distribution within the retinal microvasculature [28, 29].

Clinical evidence of the impact of IOP on retinal blood flow and velocity is inconsistent. Whilst several clinical studies have shown that as IOP increases, retinal and retrobulbar blood flow decreases, [30–32] others have not found this to hold true in various settings including post-operative trabeculectomy patients [33] and in patients treated with IOP lowering medications [34–36]. These inconsistencies are likely due to numerous factors, including arterial blood pressure and blood flow autoregulation [2] and the intrinsic difficulty of evaluating the individual contribution of these factors in a clinical setting. In organs where autoregulation is maintained, perfusion pressure is a weak parameter in altering blood flow within that organ.

In disease conditions, when autoregulation is disturbed, or absent, perfusion pressure as a determinant of blood flow becomes paramount. The role of arterial pressure and IOP can be easily understood in the following ways;


Furthermore, the picture may be complicated in cases where a state of low perfusion is maintained at the limits of autoregulation on a more chronic basis. Here there is no sudden event causing an ischemic infarct such as is seen in CRAO or PAMM, but rather there may be enough persistent venous stasis to induce a clinical picture reminiscent of Central retinal vein occlusion (CRVO), in a condition commonly known as Ocular ischemic syndrome or venous stasis retinopathy.

## **6. Effect of ocular hypertension in clinical retinopathies**

The effect of IOP in retinal vascular diseases is well documented. Ocular hypertension (OHT) is a risk factor for the development of CRVO. On the other hand, OHT seems to have a protective effect on the development and progression of DR.

#### **6.1 Retinal vein occlusions**

Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders, with a prevalence as high as 4.6% in adults 80 years or older, [38] and can be seen in the central retinal vein (CRVO) or in branched veins (BRVO). Although the underlying mechanisms governing RVOs are multifactorial, Virchow's triad teaches that a combination of blood flow stasis, endothelial cell damage and hypercoagulability leads to thrombosis [39].

In CRVOs, the proximity of the central retinal vein and artery (enveloped in a common fibrous tissue) to one another within the optic disc means that the presence of arterial disease such as systemic hypertension and arteriosclerosis, can predispose the central retinal vein to a pre-morbid low flow state. Additional risk factors for RVOs include coagulation disorders and hyper viscosity states, but one of the most frequently encountered risk factors is glaucoma/OHT. In BRVOs, hemodynamic changes occur at arteriovenous crossings coupled with altered blood flow thus leading to localized venous compression [40].

Verhoeff first described the relationship between glaucoma and CRVO in 1913, where he postulated that increased IOP compresses and collapses the wall of the central retinal vein, leading to intimal proliferation within the vein [41]. Whereas primary open angle glaucoma (POAG) is a feature which precedes CRVO in between 10 and 40% of patients, [Larsson] the prevalence of POAG in BRVO appears to be less frequent at between 6 and 15% [42, 43].

Many studies have analyzed the relationship between glaucoma and RVO risk, with contradictory outcomes. Yin et al. recently performed a meta-analysis of

### *Retinal Vascular Implications of Ocular Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98310*

research conducted between 1977 and 2015, examining the relationship between glaucoma and RVO and found glaucoma to be a core risk factor for RVO in 15 studies with high methodological quality [44]. The studies reviewed have suggested a number of different potential hypotheses;


Although glaucoma and OHT are risk factors for CRVO, once CRVO is established, there is a curious phenomenon of lowered IOP in the eye with the RVO as compared to the fellow, non-affected eye. The exact cause of this lowering of IOP is not understood, though Hayreh et al. postulated it may be due to the release of soluble factors induced by relative ocular ischemia [58].

This lowered IOP, combined with increased venous pressure, increases the capillary hydrostatic pressure according to Starling's Law [59]. This in turn leads to increased leakage from compromised endothelial cells; the clinical presentation of which is seen as macular edema and hemorrhagic retinopathy.

In fluid dynamics, Bernoulli's principle states that an increase in the speed of a fluid (kinetic energy) occurs simultaneously with a decrease in static pressure or a decrease in the fluid's potential energy. The converse is the case in severe CRVO where the venous thrombosis causes significant slowing down of blood flow velocity, the kinetic energy that drives the blood flow forward within the capillary network can be reduced enough to cause intra capillary thrombosis, as evidenced in wide spread capillary drop out on fluorescein angiography. When enough retinal area is involved (usual criteria is 10 disc areas on angiography), the resulting ischemia may lead to neovascular complications. This is referred to clinically as ischemic CRVO. At the same time, according to Bernoulli principle of total energy conservation, the decrease in kinetic energy will result in a commensurate increase in the potential energy as expressed in lateral or transmural pressure. This increase in lateral pressure causes extravasation of fluid into the interstitial space and results in retinal edema.

Whilst our current approach to the management of RVO incorporates addressing associated systemic risks common to both glaucoma and RVO, further work is needed to establish the exact effects of elevated IOP as well as the additional effect of glaucoma medications on the autoregulatory capacity of retinal blood flow e.g. timolol enhancing autoregulation and thus possibly aiding perfusion following RVOs [60].

### **6.2 Diabetic retinopathy**

DR continues to be one of the leading causes of blindness globally, and as retinal capillaries can be visualized directly, the progression of DR can be continuously assessed. The microangiopathic processes noted in the retina are echoed in the glomeruli of diabetic patients. The glomerular microcirculation has received significant attention as it's accessibility to both clinical and experimental observation is unique, in that fluid and macromolecule movement across capillary walls can be easily quantified [61]. Glomerular hemodynamic abnormalities, as with the microcirculation in the retina, are thought to be mediated by a complex chain of events including direct mechanical injury (baro-damage) to the capillaries, [62] and subsequent intracapillary coagulation [63]. As with renal microcirculation, hemodynamic abnormalities within the retinal microcirculation can be detected many years before DR becomes overt.

Multiple factors, including altered levels of vasoactive substances, altered vasomotor responsiveness and persistent hypoxia leads to marked venous vasodilation. Although the consequent elevations in capillary pressure and blood flow may be the inciting mechanism for the onset of diabetic microangiopathy, the factors linking hyperglycemia to vascular cell dysfunction, capillary dropout, tissue hypoxia, and abnormal angiogenesis, remain poorly described [64, 65]. Patients with diabetes are however known to have dysfunctional retinal perfusion [66] and an abnormal autoregulatory capacity [67].

The retinal microcirculation is sensitive to local variations in oxygen tension, with capillary blood flow and vessel diameter varying as necessary in response to local metabolic demand; [61] retinal capillaries dilate with low ambient oxygen tensions, and constrict with high ambient oxygen tensions [68].

As DR progresses, capillary microaneurysms, exudates and hemorrhages are seen, followed by endothelial proliferation with neovascularization. In the latter stages, focal retinal atrophy and vitreous body adhesions occur, eventually leading to tractional retinal detachment if not treated. These advancing stages of DR are characterized by local capillary basement membrane thickening, endothelial proliferation and intracapillary thrombosis, the latter of which further aggravates endothelial proliferation. This cascade results in capillary lumen obstruction, exacerbated even more so in the presence of hypoxia. Over time, retinal microvascular damage in the presence of persistent hypoxia results in elevated intraocular vascular endothelial growth factor (VEGF), an endothelial-specific diffusible factor that mediates permeability and development of vasculature.

That hemodynamic factors play an important role in the development of DR is evident in many clinical observations. Generally, disease states that cause an elevation in retinal perfusion pressure hastens the onset of DR. When retinopathy is already established, the same high perfusion state can cause a more rapid progression of the retinopathy. Conditions that cause perfusion pressure to increase include:

#### i.Systemic hypertension

The United Kingdom Prospective Diabetes study (UKPDS) found that improved blood pressure control decreased the progression of diabetic microangiopathy and correlated with a reduction in risk of cerebrovascular incidents by more than a third [69].

ii.Pregnancy

It is widely recognized that pregnancy worsens during pregnancy [70–72]. DR severity pre-pregnancy, metabolic control during pregnancy and pregnancy related hypertension have all be identified as risk factors for this worsening [70, 72]. Increased cardiac output and plasma volume during pregnancy, as well as a decrease in peripheral vascular resistance significantly increase blood flow to different parts of the body, including the retinal vasculature. Chen et al. have shown that when increased blood flow was documented in the first trimester, DR progressed, in contrast to unchanging DR severity in women whose retinal blood flow remained unchanged [73]. The hyperdynamic circulatory state induced by pregnancy is counteracted effectively only if normal autoregulatory control of blood flow is maintained. In some diabetic pregnant women, these mechanisms are flawed, where increased blood flow potentially inflicts endothelial damage by inciting additional shear stress at the capillary level.

Conversely, disease state that leads to a decrease in retinal perfusion pressure may protect against the development or the progression of DR.

## *6.2.1 Carotid stenosis*

It is noted that patients with carotid artery disease may have eyes with asymmetric severity of DR; with the less affected eye having an ipsilateral carotid artery that is more obstructed. The protective effect has been attributed to the reduction in the retinal arterial perfusion pressure [74]. It should be noted that when the carotid occlusion becomes severe, that is exceeding 90% of the vessel caliber, this protective effect is lost due to consequent ischemia [75].

## *6.2.2 Optic atrophy*

A similar asymmetric DR severity can be seen in patients with optic atrophy. The side with optic atrophy has severe DR compared to the side with a normal optic nerve. This can be explained by the narrowing of the retinal arterioles generally seen in eyes following the onset of optic atrophy [76, 77]. In these eyes, although the arterial pressure at the optic nerve head may not be altered, the capillary perfusion pressure is much reduced due to the narrowing of the vessel caliber.

The relation between vessel caliber and end capillary perfusion pressure can be understood through Poisseuille's blood flow equation: [78].

$$
\Delta \mathbf{p} = 8 \mu \mathbf{L} \, \mathbf{Q} / \pi \mathbf{R} \mathbf{4} = 8 \mu \mathbf{L} \, \mathbf{Q} / \mathbf{A}^2 \tag{1}
$$

where:

Δp is the pressure difference between the two ends (pressure drop) L is the length of pipe (distance blood travels to reach capillary bed) μ is the dynamic viscosity.

Q is the volumetric flow rate (blood flow).

R is the pipe radius (vessel caliber).

A is the cross section of pipe (vessel cross sectional area).

Note that the drop in perfusion pressure at the capillary level is inversely correlated to the square of the cross sectional area of the vasculature. The narrower the vessel caliber, the smaller the cross sectional area, the drop in perfusion at the capillary level is increased by the fourth power of the radius of the vessel.

#### *6.2.3 Myopia*

In patients with anisometropia where one eye is significantly more myopic than the other, it is the eye with higher myopia that demonstrates less severe DR levels [79, 80]. Myopic eyes tend to have longer axial lengths, consequently for every corresponding point in the retina, the arteriole has to travel further to reach compared to that in an eye with a normal axial length. This increased blood travel, can be simplified as having comparatively longer vessel or pipe length, with a consequent decrease in end capillary perfusion. Mathematically, we can once again understand it through Poisseuille's equation: as L increases, Δp increases also, meaning a drop in the capillary perfusion pressure.

#### *6.2.4 Ocular hypertension and glaucoma*

Whereas the clinical evidence from the above mentioned examples of asymmetric DR seems to point to the general idea that an increase in end capillary perfusion pressure is a main risk for the development or worsening of DR, studies directly examining the association between MOPP and DR are rare. Many studies have assessed the relationship between retinal blood flow and DR [81–84]. Whilst a series of studies have reported that increased retinal blood flow is associated with background DR, [81, 82] pre-proliferative DR, and proliferative DR, [81] as with RVO, data on the relationship of the effect of MOPP remains inconsistent globally. Whilst some researchers have shown higher MOPP is associated with DR, macular edema, and hard exudation, [81, 85] others did not observe this association [86].

The pathophysiology of glaucoma is not completely understood. However, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities, including the phenomenon of neurovascular coupling (NVC). Within the retina, studies have shown that not only is vascular dilatation reduced in patients with little to no DR, but also in glaucoma patients when compared to that in healthy subjects [87–89]. These studies indicate a process whereby abnormal neurovascular coupling precedes a visible angiopathy in humans in both glaucoma and DR.

Several population-based studies have shown a positive association between ocular hypertensive disorders and diabetes mellitus [90–92] whilst some shown a negative association [93, 94]. Becker et al. showed that glaucoma decreased the incidence of DR and postulated this was because the increase in IOP lowered the transmural hydraulic pressure gradient across retinal capillaries [95].

Some groups have postulated that the reduced number of retinal ganglion cells found in glaucoma lead to a reduced ischemic drive and thus prevents DR development [96, 97]. Singal et al. showed that the mean duration of diabetes with early non-proliferative changes was maximum in patients with primary open angle glaucoma (15.8 years), followed by normal tension glaucoma (14.0 years) and then in non-glaucomatous patients (13.3 years) [96]. They also observed that advanced stages of DR changes were seen more so in the group without glaucoma. These findings, alongside those of Williams et al., suggests that not only does glaucoma delay the onset of DR, but that glaucoma also has an effect in delaying the progression of DR changes [96, 97].

The protective effect of ocular hypertension and glaucoma on DR can also be understood through the hemodynamic changes.

Increased IOP causes a decrease in ocular perfusion pressure. This directly reduces endothelial baro-damage. Also, in patients with established glaucoma with significant optic atrophy, the resultant arteriole narrowing would additionally cause a significant increase in vascular resistance and a decrease in end capillary perfusion as demonstrated through Poisseuille's equation.

## *6.2.5 Pan retinal laser photocoagulation (PRP)*

PRP is an effective treatment against proliferative DR. The DRS study showed that the 5 year rate of severe vision loss from proliferative DR was reduced from 50% without PRP to 20% by this treatment, as onset and progression of neovascularization was prevented. Furthermore, PRP reduced the risk of elevated IOP during the study period thus delaying onset of neovascular glaucoma [98]. It's therapeutic effect is understood to be due to the reduction of oxygen and metabolic demand through tissue ablation. It should be pointed out that after PRP, the arteriole calibers are decreased significantly, resulting in a marked reduction of end capillary perfusion pressure.

### *6.2.6 Anti-VEGF intravitreal injections*

Development of injectable anti-VEGF agents into the eye have revolutionized the way in which diabetic macular edema and proliferative DR can be managed. Multiple pivotal trials reproducibly demonstrated significant regression of DR severity with anti-VEGF treatments, [99–101] as well as complete regression of new vessels in up to 20% of cases [102]. It has also been noted that in diabetic macular edema treatment, the number of injections needed to control macula edema decreases in the second and third year as compared to the first year of treatment [99]. These findings suggest that continued anti-VEGF, with attendant restoration of healthier hemodynamics, a reduced capillary perfusion pression and less barodamage to the capillary endothelium may confer some improvement in the severity of retinopathy.

## **7. Conclusions**

A comprehensive review of retinal hemodynamics, the interplay between various factors such as blood pressure, vascular resistance, IOP, ocular perfusion pressure and blood flow are covered in this chapter. Changes in one of more of these factors are discussed in different disease states. Specifically, we discussed two important and frequent clinical entities; CRVO and DR. IOP plays an important role in the pathogenesis of each of these two conditions. In eyes with predispositions to venous stasis, IOP causes a further reduction in ocular perfusion and thus exacerbates the stasis. On the other hand, in diabetic microangiopathy, the endothelium is damaged, so that an increased IOP with attendant reduction in perfusion pressure actually protects the endothelium from transmural pressure related trauma.

## **Conflict of interest**

The authors declare no conflict of interest.

*Ocular Hypertension - The Knowns and Unknowns*

## **Author details**

Fidan Jmor and John C. Chen\* Department of Ophthalmology and Visual Sciences, McGill Academic Eye Centre, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

\*Address all correspondence to: johnchen.mcgill@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Retinal Vascular Implications of Ocular Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98310*

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## **Chapter 3**

## Progression from Ocular Hypertension into Glaucoma

*Sayantan Biswas*

## **Abstract**

Ocular hypertension (OHT) is characterized by raised intraocular pressure (IOP) >21 mmHg without any visual field (functional) or optic nerve (structural) defect featuring glaucoma. Raised IOP is a major risk factor of glaucoma and a proportion of eyes with OHT progresses into primary open angle glaucoma. Glaucoma is a debilitating disease with potential for blindness if left untreated and associated reduction in the quality of life of the affected individual. It is challenging for the clinicians to decide whether an OHT will progress into glaucoma or not based on the risk factor model of the Ocular hypertension treatment study. Moreover, the question whether only IOP or a myriad of factors like central corneal thickness, baseline IOP, visual field, family history of glaucoma, ocular biomechanics are all important in determining the progression is yet to be answered. The rate of progression is also important and needs analysis for further discussion. Summarizing the landmark studies on ocular hypertension and glaucoma to date are imperative in this regard. This chapter presents the overview of OHT and its possible etiology and pathophysiology, risk factors, clinical tests evaluating OHT eyes and elaborates on the progression of OHT to glaucoma over time in relation to the treatment.

**Keywords:** Ocular hypertension, pathophysiology, risk factors, progression, treatment

## **1. Introduction**

Elevated intraocular pressure (IOP) is an important and the only clinically modifiable risk factor of glaucomatous optic neuropathy [1–4]. Clinically, ocular hypertension (OHT) is most widely defined as raised IOP of > 21 [5] or ≥24 [6] mm Hg in eyes without detectable glaucomatous visual field (VF), optic nerve (ON) or retinal nerve fiber layer (RNFL) damage [6, 7]. It may be also defined as IOP in the highest 97.5% percentile for the population without having optic disc or visual field damage [8]. The prevalence of OHT worldwide varies between 0.32-12.2% [9–15].

Ocular hypertensives have been studied widely through several clinic and population-based studies. The two earliest prospective studies are done by Quigley et al [2] and Georgopoulos et al [16] on large cohort of OHT patients. The first one is the follow-up of 647 OHT patients with IOP >21 mm Hg for 6.2 years. VF testing using Goldmann perimeter (static & kinetic) was performed yearly once [2]. The other study was on 345 untreated patients with OHT (IOP≥21 mm Hg) for a mean duration of 7.3 (6-8) years. VF testing was done every 6-10 months using Humphrey VF analyzer 30-2 program [16].

Ocular hypertension treatment study (OHTS) is the largest multicenter randomized trial involving 1636 OHT participants (aged 40-80 years, IOP 24-32 mm Hg) randomized to either ocular hypotensive drug or to stay under observation for a follow up period of 7.5 years. They were followed up with Humphrey VF 30-2 every 6 months and stereoscopic optic disc photographs every 12 months. Treatment goal was IOP reduction by 20% or more and an IOP of ≤24 mm Hg. The average reduction of IOP achieved with medication was 18.4% which is equivalent to 4.6 mm Hg. In the second phase of the study, the two groups of medication and observation was treated with IOP lowering drugs for another 5.5 years (total 13 years), creating an early treatment and delayed treatment groups [6, 7, 17].

Most population-based studies have shown 9.5-17.4% of OHT eyes develop primary open angle glaucoma (POAG) without treatment over 5 years [6, 17, 18]. Around 1.5-10.5% of these untreated OHT eyes stand at a risk of going blind over the next 15 years [19]. Even after treatment, 4.4% of OHT eyes develop POAG [17] while 0.3-2.4% eyes still carry the risk of becoming blind [19]. Hence, OHT poses a significant socio-economic impact with potential to debilitate the quality of life (QoL) of the diagnosed person once the disease starts progressing [20–24].

## **2. Pathophysiology**

Lamina cribrosa (LC) is a sieve-like structure, which creates a perforation in the sclera through which the axons of the retinal ganglion cells (RGC) exit the eye as optic nerve fibers. The lamina is the weakest point in the wall of the eye. IOP is believed to cause mechanical stress and strain on the LC at the posterior structures of the eye [25]. This results in the compression, deformation and remodeling of the LC at the optic nerve head (ONH) along with axonal damage and blockade of RGC axonal transport (both orthograde and retrograde) to the lateral geniculate nucleus (LGN) [26–28]. It is followed by apoptotic degeneration and death of RGC of the retina and the optic nerve causing vision loss [29].

In experimental glaucoma, disruption of axonal transport causes the collections of vesicles and disorganization of microtubules and neurofilaments in the prelaminar and postlaminar regions [29]. Postmortem of human eyes with glaucoma also revealed these ultrastructural changes in the optic nerve fibers [25]. It was shown that the pressure gradient between the intraocular pressure and cerebral spinal fluid pressure at the lamina cribrosa might be influential in maintaining blood flow in the optic nerve head [30]. When the pressure gradient is increased, the axonal transport would be disrupted, leading to retinal ganglion cell damage. In fact, the degree of RGC death is related to the level and duration of intraocular pressure elevation [29].

This strain also initiates a cascade of molecular and neurotransmitter changes in the surrounding cells of the retina and optic nerve (like astrocytes, microglia, horizontal and amacrine cells, etc.) which alters the microcirculation and remodels the extracellular matrix [29]. Further atrophy and death of the target relay neurons occurs in the magnocellular and parvocellular LGN [28].

The intraocular pressure is a function between the production of aqueous humor from the ciliary processes of the ciliary body and its outflow through the trabecular meshwork (TMW) via schlemm's canal (conventional pathway) and the uveoscleral pathway via ciliary muscle/choroid/sclera (unconventional pathway) [29, 31]. There is an increased resistance found in the aqueous humor outflow through the TM lead conventional pathway in OHT eyes [29, 32]. Thus, resulting in an increase in the IOP, which causes the mechanical stress and strain on the posterior structure of the eye as described.

*Progression from Ocular Hypertension into Glaucoma DOI: http://dx.doi.org/10.5772/intechopen.98886*

The average IOP which results from a balance between the normal production and outflow of aqueous humor, which is around 14-15 mm Hg [31, 33]. Although, it is almost impossible to define what is a normal or safe IOP as all individual eyes are uniquely susceptible to the damage caused by IOP. Eyes do not develop any glaucomatous damage in spite of relatively high IOP, whereas, others get damaged even under normal or even relatively low IOP [34, 35]. The result of genetic predisposition and risk factors working alone or their interactions along with the biomechanical properties of the ONH and the scleral connective tissue are hypothesized to account for the susceptibility of individuals under high, normal or low IOP [26].

Secondary damage may occur consequential to RGC death due to the release of glutamate and glycine from the injured neurons leading to excitotoxic damage [36, 37]. Production of nitric oxide may result in oxidative damage to the RGCs and their axons [38–42]. Tissue ischemia-hypoxia is another implicated factor related to glaucomatous optic neuropathy [43, 44]. Reduced ocular perfusion pressure, which is dependent on the systolic and diastolic blood pressure is also found to be associated with higher incidence of OAG [45–47]. Other causes are vascular insufficiency and autonomic dysfunction of the ONH [48–51].

## **3. Risk factors**

#### **3.1 Age**

Age is major factor positively associated with the IOP [52]. The Los Angeles Latino Eye Study found higher prevalence of OHT among older Latinos than in younger Latinos (P < 0.0001) [53]. Latinos aged ≥80 years had a 3-times higher prevalence than the younger ones (40-49 years) [10]. The OHTS [6] and European Glaucoma Prevention Study (EGPS) [54] found older age (per decade) to have higher risk of progressing from OHT into POAG (hazard ratio (HR) 1.22, P < 0.05 and 1.32, P < 0.05 respectively). Similarly, a 6 year follow up of urban Australian patients with POAG & OHT to show a significant association of age with the prevalence of POAG [55] and Malmo¨ Ocular Hypertension Study (MOHS) [56] also found older age (per year) as a predictive factor (HR 1.32, P < 0.05 and 1.05, P = 0.034) of developing POAG among OHT patients in their multivariate analysis.

#### **3.2 Intraocular pressure**

IOP is the strongest risk factor associated with glaucoma such that it is regarded as causality. The dose-response relationship has been well documented and demonstrated in several prevalence and longitudinal studies [7, 57–59]. OHTS demonstrated that 23% reduction in the IOP can decrease the incidence of POAG by 60% [7]. Similarly, the Melbourne Visual Impairment Project estimated that for every 1 mm Hg, the risk for glaucoma increased by 10% [60]. Also, the Early manifest Glaucoma Trial (EMGT) and the Collaborative Normal Tension Glaucoma Study (CNTGS) reported an IOP reduction of 25% and greater than 30% can lower the risk of progression by 33% and 50%, respectively, compared to those with no treatment [61, 62]. The Advanced Glaucoma Intervention Study (AGIS) also reported a reduction of IOP to be associated with stable visual fields [57]. A retrospective cohort analysis of 230 OHT patients over 5 years revealed that higher peak IOP is a risk factor for developing POAG in the multivariate analysis. Both the peak IOP and the mean IOP in the progressed group was higher than in the stable group (P < 0.01) [63]. IOP per mmHg presented with HR of 1.14 (P = 0.047) for developing POAG among OHT eyes in MOHS [56].

## **3.3 Central corneal thickness**

OHTS confirmed thinner central corneal thickness (CCT) to be associated with greater risk of conversion into POAG from OHT [6]. The risk increased by 71% for every 40 μm decrease in the CCT (Multivariate HR 1.71, P < 0.05). Similarly, the EGPS found lower CCT by 40 μm to have higher risk (HR 1.32, P = 0.018) of POAG [54]. Eyes with thickness ≤555 μm had 3 times increased risk of developing POAG than those with CCT >580 μm [6]. This was probably because thicker cornea has an actual (true) IOP which is lesser than the measured IOP. Conversely, thinner cornea has a true IOP which is higher than measured IOP. Thus, eyes with thicker cornea stand at a risk of getting misdiagnosed as OHT. However, we do not know whether the corneal thickness is associated with factors affecting susceptibility to glaucoma or not.

## **3.4 Corneal parameters and intraocular pressure and**

Corneal properties such as thickness, astigmatism, curvature, hysteresis and biomechanics poses a challenge in measuring the true IOP [64–66]. The Goldmann applanation tonometer (GAT) is known to falsely elevate IOP in thick cornea and falsely reduce IOP in thin corneas [67, 68]. The IOP values measured using CorVis ST is shown to remain almost unaffected by corneal parameters like its thickness and topography through a wide range of IOPs. CorVis ST IOPs were validated on ex-vivo human donor eyes [69, 70]. Corneal characteristics are believed to be strong confounding factors in the measurement of true IOP [70].

#### **3.5 Race**

In Phase 2 of OHTS, POAG developed more commonly among African-Americans in the univariate analysis but loses its significance on adding vertical cup to disc ratio (VCDR) and CCT into the multivariate model [6, 17]. However, with similar baseline IOP, follow up IOP and treatment, African Americans have higher risk of developing POAG. This suggests that black race is not associated with an increased risk of glaucoma progression. However, the higher prevalence of other risk factors of glaucoma is present in black individuals such as thinner central corneal thickness (CCT), higher IOP, larger VCDR than their white counterparts [71–73]. Self-reported black race was also identified as an independent risk factor of developing optic disc hemorrhage after 13 years of follow up in OHTS [74].

## **3.6 Gender**

Although males with OHT presented with a higher risk of POAG in the univariate analysis of OHTS (OR 1.87, P<0.05), it was not significant in the multivariate model [6]. However, other studies on OHT & POAG patients found male sex to have higher odds of having POAG than females (OR 1.9, P <0.01) [55].

#### **3.7 Family history**

OHTS failed to find any association of OHT progression with family history of glaucoma [6]. On the other hand, Landers et al studied 301 OHT and 438 POAG patients and reported family history of glaucoma to be a risk factor of having POAG (Odds ratio 1.6, P < 0.01) [55]. Similarly, an earlier study on 345 OHT patients revealed that out of 31.6% with family history of glaucoma, 55% developed POAG (P < 0.001), which shows family history (heredity) as an important factor in the development of glaucoma [16].

*Progression from Ocular Hypertension into Glaucoma DOI: http://dx.doi.org/10.5772/intechopen.98886*

#### **3.8 Myopia**

OHTS have found no association between myopia and POAG [6]. However, earlier studies involving patients with OHT and myopia were found to develop glaucoma more than those without myopia [75, 76]. Landers et al. studied patients with POAG (n = 438) and OHT (n = 301) with SAP for a duration of 6 years and reported that myopic patients (SE ≤ -1 D) with OHT have 1.5 times higher risk of developing POAG [55]. Georgopoulos et al. studied 345 untreated OHT with SAP over a period of 7.3 years and found axial myopia (0.001 < P < 0.01) to be a risk factor for the development of glaucoma [16]. Similarly, the Casteldaccia Eye Study on 44 OHT/POAG (IOP ≥ 24 mmHg) and 220 controls (IOP ≤ 20 mm Hg) found myopia to be associated with increased (multivariate OR 5.56) of OHT/POAG [77].

Quigley et al. followed 647 OHT patients (40% under treatment) with refractive errors in the range between +12 and -12 D for a period of 6.2 years with Goldmann kinetic perimeter. They showed that there was no association between refractive error and visual field progression [2].

Similarly, the Malmo¨ Ocular Hypertension Study randomized 90 OHT patients to topical timolol or placebo and observed every 3 months for 10 years to conclude that myopia have no influence on the visual field progression. In their cohort, 35% of the myopes progressed compared to the 54% of non-myopes, and there was no significant association between refractive error and VF loss in OHT patients [56].

### **3.9 Optic disc hemorrhage**

Optic disc hemorrhage (ODH) in OHT eyes was associated with a 3.7 times higher risk of developing into POAG (P < 0.001) in multivariate model which included the baseline factors predictive of POAG. The incidence of POAG in eyes with and without ODH were 13.6% and 5.2% respectively after 8 years of follow up of OHTS [78]. European Glaucoma Prevention Study (EGPS) also established ODH as an independent risk factor of POAG with HR of 1.97 [79]. After the end of the 13 years follow of OHTS, it was further confirmed in the multivariate analysis that ODH has a 2.6-fold increased risk of converting to POAG (P < 0.0001) [74].

## **4. Visual field testing**

Standard automated white-on-white perimetry (SAP) is the most extensively investigated tool for assessment of visual field defects in glaucoma. In SAP, visual sensitivities at pre-defined locations of the retina are measured and compared with age-corrected normative values to detect locations of abnormal visual field sensitivity. SAP employs white stimuli on a white background to quantify visual sensitivity [80]. Visual field parameters including the mean deviation (MD), pattern standard deviation (PSD) and visual field index (VFI) [81] are global indices for measurement of average visual sensitivity and function of an eye. MD is calculated by weighting and averaging the differences of sensitivity thresholds for all the tested points between a subject's thresholds and the normative values. A negative MD indicates overall depression in visual sensitivity. PSD is an index indicating the uniformity of visual field sensitivity. It is determined by comparing the differences between adjacent points. A high PSD value indicates focal visual field loss. A low PSD value, however, can be found in a normal visual field or in an eye with diffuse loss in visual sensitivity. VFI is a percentage of overall visual field sensitivity compared with the normal age-adjusted visual field. VFI has been shown to be less influenced by cataract compared with MD [81]. The severity of glaucomatous

damage can be classified into mild (MD ≥ -6 dB) and moderate-to-advanced (MD <-6 dB) according to the Hodapp-Parrish-Anderson criterion [82]. Glaucoma hemifield test (GHT) [83] is another important parameter incorporating into SAP for glaucoma detection. GHT is calculated by the comparison of five clusters of corresponding test points between the superior and inferior fields. GHT reports the asymmetry of visual field defects in glaucoma. Three categories of visual field are classified by GHT: "within normal limits", "borderline" and "outside normal limits". Yet, a "within normal limits" visual field does not always represent a normal field. Although SAP has been proven to be useful for detection and monitoring of glaucoma [84], early stages of glaucomatous damage may appear as normal in SAP. Because of specific visual function of retinal ganglion cells (RGC) subtypes, selective perimetry can isolate the specific RGCs populations, which was found to detect glaucoma earlier than SAP. There are mainly two types of function-specific perimetries, short-wavelength automated perimetry (SWAP) and frequency doubling technology (FDT). SWAP selectively tests RGCs that target the koniocellular sublayers of the lateral geniculate nucleus by projecting blue stimulus on yellow background. In longitudinal studies, it can detect glaucoma as early as 5 years compared to standard perimetry [85–87]. FDP tests large diameter retinal ganglion cells that target magnocellular layers of the lateral geniculate nucleus and can also detect glaucoma earlier [85, 86, 88]. In a study comparing the diagnostic capability among SAP, SWAP and FDT for detection of early glaucoma (MD > -6 dB), the sensitivities were 46%, 34% and 52% respectively, with specificity ≥97% [89].

In clinical practice, SAP remains the most widely used visual field assessment for diagnosing and monitoring glaucoma. Detecting VF progression (change) over time is difficult and challenging owing to the fact that VF result are largely influenced by several factors [90–95]. Most studies formulated their own criteria to detect VF change with their own merits and demerits [96].

#### **4.1 Visual field testing in ocular hypertensives**

Although, optic disc photographs detected most (55%) of the early glaucomatous changes, almost one third had visual field changes as their earliest glaucomatous change in OHTS [7]. Soliman et al evaluated the diagnostic sensitivity of standard automated perimetry (SAP), frequency doubling technology (FDT) perimetry (C-30 full threshold) and short wavelength automated perimetry (SWAP) for the detection of glaucoma damage [97]. The diagnostic performance among FDT perimetry, SWAP and SAP were compared in 42 patients with early to moderate glaucoma, 34 with ocular hypertensives, 22 glaucoma suspects, and 25 normal controls. They found that FDT had similar sensitivity in detecting visual field abnormality compared with SAP but SWAP had a poorer performance in distinguishing the normal group from glaucoma group. The study outcomes were based on measurements of MD, PSD, and percentage of abnormal points. In glaucoma patients, whose baseline SAP was abnormal, FDT perimetry and SAP detected more abnormal points than SWAP. FDT perimetry detected larger defects in ocular hypertension and glaucoma suspects, who showed a normal baseline SAP.

Johnson et al compared automated perimetry and SWAP in a group of ocular hypertension patients and found that SWAP deficits represent early glaucomatous damage and may be related to early changes that occur at the optic nerve head [98].

Bengtsson and Heijl compared the ability of SITA SWAP, full threshold SWAP and SAP (SITA Fast) in patients with ocular hypertension, suspicion of glaucoma (glaucomatous optic disc changes but found no evidence of visual field defect on SITA standard 30-2 SAP) and early manifest glaucoma subjects (repeatable visual *Progression from Ocular Hypertension into Glaucoma DOI: http://dx.doi.org/10.5772/intechopen.98886*

field loss on GHT results) [99]. No significant difference was found between the three algorithms in detecting glaucomatous visual field abnormality. SITA SWAP was able to identify as much visual field loss as the full threshold SWAP but with a considerable reduction of test time.

In OHTS, global and localized rates of VF change were calculated from 780 eyes of 432 OHT patients based on linear regression between MD and time, and between threshold sensitivity values for each test location and time, respectively. It was noted that both the global and localized rates of VF decreased significantly (P < 0.01) over a mean of 14 years [100]. Pattern standard deviation or PSD is a weighted standard deviation of the differences between the measured and normal reference visual field at each test location. A high value represents irregularity which can be both due to focal loss in the VF or variability in the patient's responses. Hence, the use of PSD in OHTS has been criticized as it is highly variable and may add a source of error for the baseline as well as the follow up VF measurements [101].

## **5. Risk factors of visual field progression in OHT**

Elevation of IOP has been consistently demonstrated in major clinical trials as a key risk factor for both the development and progression of glaucoma. Baseline IOP, average IOP during follow-up, and fluctuation of IOP has all been reported to be associated with glaucomatous visual field deterioration [6, 102]. Five baseline factors namely, older age, higher IOP, thinner central corneal thickness, larger VCDR and higher visual field pattern standard deviation (PSD) had greater risk of conversion from OHT to POAG [6, 17]. This model was reconfirmed and validated by two independent study population of the EGPS and Diagnostic Innovations in Glaucoma Study (DIGS) [103, 104]. Disc hemorrhage is another important risk factor of visual field progression in ocular hypertension and glaucoma patients [59, 79, 105]. The role of central cornea thickness in glaucoma progression is controversial. EMGT suggests an increased risk of progression in patients with a thinner CCT [106, 107]. Central corneal thickness is a known risk factors of visual field progression in patients with ocular hypertension with 70% increase in risk with every 40μm decrease in corneal thickness [6]. However, as shown in other studies, the association of CCT with visual field progression may not be significant [108, 109].

Other potential risk factors of visual field progression in glaucoma include age, bilaterality, exfoliation, lower systolic perfusion pressure and blood pressure [110–112].

## **6. Assessment of visual field (functional) progression in OHT**

#### **6.1 Trend-based analysis**

Trend-based analysis has been used to detect localized and global loss in visual field. MD and visual field index (VFI) are global indices that have been used to estimate the overall rate of visual field progression. The pointwise linear regression (PLR) was first introduced to evaluate visual field progression by Fitzke et al. where the luminance sensitivity of every location from the entire visual field within a series of examination against time was analyzed. PLR has been shown to have a good agreement with Humphrey STATPAC-2 (glaucoma change probability analysis) in separating progressive from stable retinal locations (Kappa = 0.62) [113].

In OHTS, the global and localized VF change rates of 780 eyes from 432 OHT patients over a period of 13 years were calculated based on linear regression between MD and time, and between threshold sensitivity values for each test location and time, respectively. The significant decrease of both the global (MD) and localized rates of VF was recorded (P < 0.01). The predetermined criteria of -0.5 dB/year were met in 18.1% eyes. The rate of VF progression before and after the initiation of treatment was -0.23 vs. -0.06 dB/year [100]. The mean rate of change of MD was -0.08 ± 0.20, -0.26 ± 0.36 and -0.05 ± 0.14 dB/year for all, POAG and non-POAG eyes in OHTS (P < 0.001) [96].

#### **6.2 Event-based analysis**

The pattern deviation map and the total deviation map have been used to detect visual field progression in clinical practice and in glaucoma clinical trials. In the Early Manifest Glaucoma Trial (EMGT), visual field progression, measured by event-based analysis, was the primary outcome measurement of the study. The frequency of visual field progression was compared in 255 early glaucoma patients with and without treatment (treated with trabeculoplasty and betaxolol hydrochloride eye drops). To determine visual field progression, the follow-up visual fields were compared with the average of 2 baseline visual fields in the same eye using glaucoma change probability maps (GCPMs). GCPMs detects significant visual sensitivity worsening at P < 0.05 at each of 76 test point locations in the visual field. The EMGT uses pattern deviation GCPMs, rather than the standard total deviation GCPMs, to limit the impact of generalized loss in visual sensitivity secondary to cataract. Definite EMGT visual field progression was defined as at least 3 test points showing significant progression, as compared with the baseline, at the same locations on 2 consecutive GCPMs [62, 114]. The EMGT criteria have been incorporated into the Humphrey Field Analyzer Guided Progression Analysis (GPA, Carl Zeiss Meditec, Dubin, CA). The EMGT criteria have been reported to identify progression earlier than the visual field progression criteria used in AGIS and Collaborative Initial Glaucoma Treatment Study (CIGTS) [84].

## **7. Assessment of structural progression in OHT**

HRT I was used in the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to OHTS which included 865 eyes from 438 participants with ocular hypertension. Forty-one eyes from 36 participants developed POAG based on confirmed visual field defect or optic disc glaucomatous change with a median follow-up time of 48.4 months. Several baseline topographic optic disc measurements taken by HRT I were significantly associated with the development of POAG in both univariate and multivariate analyses, including cup-disc area ratio, mean cup depth, mean height contour, cup volume, reference plane height, and smaller rim area, rim area to disc area, and rim volume. In addition, the classification "outside normal limit" by Moorfields regression analysis (MRA) was also associated with POAG development. It was suggested that HRT I was useful in glaucoma prediction and can be used in glaucoma progression monitoring [115]. The same research group further compared the performance between the baseline glaucoma probability score (GPS) and MRA on predictive ability of conversion from OHT to POAG. Sixty-four eyes of 50 OHT subjects converted to glaucoma based on repeatable visual field defect or optic disc change with a median follow-up time of 72.3 months. In a multivariate analysis, "outside normal limits" global and sectoral baseline GPS showed significant association with the development of POAG with HR ranging from 2.92

to 3.70. In addition, baseline MRA parameters also showed significant association with POAG development with HR ranging from 2.41 to 11.03. It was concluded that both GPS and MRA showed similar performance in predicting the conversion of glaucoma from OHT subjects [116].

In the study by Strouthidis et al on 198 OHT and 21 normal subjects, rim area (RA) progression was calculated with linear regression of sectoral RA/time, defined as slope>1%/year; visual field progression was calculated by PLR of sensitivity/time. The specificities of RA were estimated from 88.1% to 90.5% with the less-stringent criteria, which were as high as the specificities of visual filed progression (85.7% to 95.4%) when standard criteria were used, indicating that both VF and HRT RA trend analysis had relative high specificities for glaucoma progression detection [117]. Although rim area has been shown to be useful for evaluating glaucoma progression, the agreement between rim area progression and visual field progression was often poor [118].

Event-based analysis is also useful for evaluation of rim area progression. In the study by Fayers et al, rim area change was determined using the rim area repeatability coefficient. The specificities were between 76.2% and 100% using different criteria to define rim area progression in 21 normal subjects. One hundred ninety-eight ocular hypertensive subjects were enrolled, 16.2%-45.4% of them were identified to have rim area progression based on different criteria with event-based analysis and 12% showed rim area progression based on trend-based analysis. To evaluate rim area progression, event-based analysis showed a higher progression detection rate than trend-based analysis [119].

GPS has also been used to evaluate glaucoma optic disc progression. Examining the linear regression analysis between GPS and time in 198 OHT subjects, Strouthidis et al showed that 25 subjects (12.6%) progressed by GPS with a significant negative slope (P<0.05); 11 of them (5.6%) also showed progression by VF with PLR analysis [120]. Twenty-six subjects (13.1%) had visual field progression alone. The specificity of GPS for glaucoma progression ranged from 95.2% to 96.8%. The conclusion is that the global GPS progression algorithm performs at least as well as previously described rim area-based HRT progression analysis [120]. Higher baseline GPS has been shown to be a risk factor for glaucoma progression in the study by Alencar et al. Two hundred and twenty-three patients with suspected glaucoma were included and followed up for an average of 63.3 months. Fifty-four (24.2%) eyes converted to glaucoma based on repeatable visual field defects and/or optic disc deterioration. Both higher values of global GPS and subjective stereophotograph assessment (larger cup-disc ratio and glaucomatous grading) were predictive of conversion, the adjusted HRs were 1.31 for global GPS, 1.34 for CDR, and 2.34 for abnormal grading, respectively. GPS performed as well as subjective assessment of optic disc in predicting glaucoma progression [121].

## **8. Features of optic nerve head progression**

Using serial optic disc photographs of 259 patients with elevated IOP followed over 15 years, Pederson et al showed that progressive enlargement of the optic cup was commonly the first sign of glaucoma progression [122]. Tuulonen et al detected equal numbers of glaucomatous eyes with diffuse and localized enlargement of optic disc cup in 61 patients with ocular hypertension [123]. In the study by Odberg et al, progressive optic disc cupping occurred most frequently in the superotemporal or inferotemporal quadrants [124]. Lloyd et al examined serial optic disc photographs of 336 eyes of 168 patients with ocular hypertension or early glaucoma [125]. Optic disc progression was defined as: new or increased neuroretinal rim (NRR)

narrowing (2 or more clock hours), notching (1 clock hour or less of narrowing of the NRR), optic disc excavation (undermining of the NRR or disc margin), or development of nerve fiber layer defect. Ninety two of 336 eyes (27.4%) showed optic disc progression after a median of 6.1 years of follow-up. Among those with progression, excavation occurred most commonly (89% of eyes), followed by rim narrowing (54% of eyes) and notching (16%). The inferotemporal quadrant of optic nerve head was the most common location for glaucoma progression [125].

Expansion in the size of peripapillary atrophy was related to glaucoma progression and conversion from ocular hypertension to glaucoma [126, 127].

Another important sign relevant to glaucoma assessment is peripapillary atrophy (PPA). The α zone PPA is located peripherally and characterized by irregular hypopigmentation and hyperpigmentation in the retinal pigment epithelium whereas β zone PPA is close to the optic disc border and characterized by a complete loss of retinal pigment epithelium [128]. Both normal subjects and glaucoma patients can develop α zone and β zone atrophy but the PPA, especially β zone PPA, is larger and more common in glaucoma patients [129]. PPA has been shown to be highly correlated to glaucomatous change [129] and its expansion is also related to glaucoma progression and conversion from ocular hypertension to glaucoma [126].

## **9. Features of optic nerve head changes**

ONH cupping can be due to a combination of NRR loss, lamina cribrosa deformation and prelaminar surface tissue loss. Localized NRR loss can be observed as narrowing or notching of the rim, which is most frequently found in the inferotemporal and supero-temporal sectors of the optic disc [25, 130]. Progressive enlargement of the optic cup is an important sign of glaucoma progression, as shown in a study examining serial optic disc photographs in 259 patients with elevated IOP followed over 15 years [122]. Tuulonen et al studied 61 patients with ocular hypertension and reported an equal number of eyes with diffuse and localized progressive enlargement of the optic disc cup in eyes developed glaucoma over the follow up period of 10 years [123]. Odberg et al reported the supero-temporal and infero-temporal quadrants as the most frequent locations of progressive optic disc cupping [124]. Lloyd et al studied 336 eyes of 168 patients with ocular hypertension or early glaucoma for a median of 6.1 years of follow-up. They examined serial optic disc photographs and showed that for the 92 eyes (27.4%) showing optic disc progression, optic disc excavation occurred most commonly (89% of eyes), followed by rim narrowing (54% of eyes) and notching (16%). The inferotemporal quadrant of optic nerve head was the most common location for glaucoma progression [125]. In OHTS, 69 eyes had optic nerve damage alone without visual field changes. This included 55% of patients reaching the study endpoint [7]. Airaksinen et al [131] followed up 75 OHT patients for 5-15 (mean 10) years using a computerized planimeter and found a decrease in the rim area among 57% of OHT patients. Loss of RA per year was 0.47% and 2.75% among stable and progressing OHT respectively. The loss of RA was linear in half of the patients (49%), with rest as episodic (22%) and curvilinear (29%) [131].

However, it should be remembered that both OHT and EGPS used serial optic disc stereophotographs to measure the vertical CDR which is known to have high intra- and inter-observer variability among clinicians [132]. Moreover, the current optic disc imaging and measurement techniques namely HRT & OCT neither correlate well with stereophotographs and nor with the disc margin (which coincides with the Bruch's membrane opening or BMO) [133–135]. This disagreement in the VCDR measurement might give rise to variable result of OHT progression into

POAG [136]. Although, BM is a stable ONH structure and is less affected by age or increasing IOP, eyes with high myopia often have poorly visible BMO and overhanging BMO due to the BM shift [137–139].

## **10. Progression of ocular hypertension**

Overall, 90% to 95% of patients with ocular hypertension did not go on to develop Glaucoma. After 5 years, 4.4% and 9.5% developed POAG under the medication and observation group respectively in phase 1 of OHTS. Use of medication was protective against POAG with a HR of 0.40 (95% Confidence Interval (CI): 0.27-0.59, P < 0.0001) compared to those under observation. The treatment had significant effect on both the optic disc and visual field changes. Early treatment of OHT reduces the 5-year incidence of POAG by 60% [6, 17].

In the 2nd phase of OHTS, the two groups of medication and observation were both treated with IOP lowering drugs for another 5.5 years (total 13 years), creating an early treatment and delayed treatment groups. There is a linear risk of OHT converting to POAG over 15 years. Cumulative proportion of study participants developing POAG was 0.16 vs 0.22 (P = 0.009) in early treatment vs delayed treatment groups. The median time to develop POAG was delayed in the early treatment groups than the delayed ones (8.7 vs 6 years) [17, 74, 140].

Starting treatment after the appearance of early signs of POAG do not have any significant negative effect on visual field loss over next 5 years, given the patients follow up regularly. Clinicians need to assess both the structural and functional parameters in OHT eyes to determine disease status and progression [6, 7, 17].

DIGS also found the predictive model suggested by OHTS to be useful to assess the 5-year risk of developing POAG among their independent population of 126 OHT patients [104]. DIGS also found long term IOP fluctuation not associated with risk of developing POAG in untreated OHT subjects (multivariate HR 1.08, P = 0.62). However, mean IOP, i.e., the level of IOP during follow up was significantly associated (HR 1.20 per 1mm higher, P = 0.005) [141]. Similarly, MOHS with 10-17 years of follow up of their OHT patients also found mean IOP level (HR 1.21, P = 0.005) to be significantly associated with increased risk of POAG, but not IOP fluctuation (P = 0.49) [142].

## **11. Treatment**

OHT and POAG treatments are mainly focused at using topical prostaglandin analogs to increase the uveoscleral outflow pathway [143, 144]. Prostaglandin analogs are quite potent IOP lowering drugs which are well tolerated without much side effects and require only one dose at night to cover the nighttime peak IOP hours [144]. However, some patients still require adjunctive therapy with other drugs as topical beta-adrenergic antagonists (suppresses aqueous production), alpha-adrenergic agonists (suppresses aqueous production + increases uveoscleral outflow), and carbonic anhydrase inhibitors (suppresses aqueous production) [143, 144].

Clinical trials on topical hypotensive drops showed Latanoprostene bunod 0.024% to have a significantly better IOP lowering effect compared to either latanoprost 0.005% or timolol 0.5% over 1 year among European, North American and Japanese patients with OHT/POAG [145, 146]. The side effect profiles were similar among the medications [144].

A multicenter randomized controlled trial (Laser in Glaucoma and Ocular Hypertension trial or LiGHT) compared ocular hypotensive drops (588 eyes) vs selective laser trabeculoplasty (SLT) (590 eyes) in newly diagnosed OHT and POAG patients. This RCT was unique in its novel approach of including QOL as an outcome measure and defining the target IOP, which was specific for each individual based on their disease severity and risk of vision loss. Moreover, target IOP was adjustable based on IOP control and disease control which resembles common clinical practice more than a fixed algorithm [147, 148]. It was found that eyes treated with medicine first progressed faster compared to the laser first eyes. Total deviation (both pointwise & global) as well as pattern deviation had a greater risk of progression (risk ratio 1.37-1.55, P < 0.001) in the medicine first group than the laser [149]. The efficacy between SLT (611 eyes) and topical hypotensive drug (622 eyes) among eyes with OHT and POAG over 3 years were assessed through another randomized controlled trial. They found both SLT and medication to be equally effective in lowering absolute IOP in both OHT and POAG eyes. IOP control without eye drops was achieved in 75% of eyes after 1-2 SLTs [150].

Benefits of early treatment are more in high-risk patients (determined using the five-factor model of age, IOP, CCT, CDR and visual field PSD) than those with low risk. No benefit of early treatment was found for patient in the low-risk group [17].

EGPS failed to find any significant difference in IOP among OHT patients with and without dorzolamide after 5 years. Dorzolamide reduced IOP by 15-22%, whereas, the IOP in placebo group also got reduced by 9-19% (HR < 1, P > 0.05) [103].

## **12. Conclusion**

There are several risk factors associated with the progression of OHT into glaucoma. Measurement of the true IOP is an important aspect of distinguishing patients with OHT from those with normal IOP and thicker cornea. Patients with OHT must be first evaluated and classified as having high risk or low risk of glaucoma. Only high risk OHT eyes poses a major threat of progressing into glaucoma. However, there are inherent limitations which must be considered while using the five-factor model. A better formulation of the risk assessment technique is warranted for more practical classification of OHT in clinics. Treatment with ocular hypotensive drugs or laser on high-risk patients is an effective way to reduce the risk of OHT eyes progressing into glaucoma.

## **Author details**

Sayantan Biswas Singapore Eye Research Institute, Singapore

\*Address all correspondence to: sayantanbiswas@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Progression from Ocular Hypertension into Glaucoma DOI: http://dx.doi.org/10.5772/intechopen.98886*

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## **Chapter 4**
