When to Treat Ocular Hypertension?

Abstract

How to decide which patient should receive treatment to prevent conversion to glaucoma? Ocular hypertension is the only treatable risk factor for glaucoma, yet not all patients with hypertension develop glaucoma, and not all glaucoma patients have ocular hypertension. Deciding when and how to start treatment can be challenging, particularly in patients without other risk factors. When facing this dilemma one should ponder: the patient’s risk tolerance/avoidance, the prospect of long-term topical treatment including adverse effects, the psychological and economical burden of a pre-disease state and its treatment, treatment compliance, and the possibility of over-treating. New tools such as AI-guided image analysis, improved testing algorithms, and novel minimally invasive treatments may help control and weigh this risk factor more conveniently, avoiding over-treatment but preventing glaucoma-related blindness.

1. Introduction

Ocular hypertension is the most recognizable risk factor for glaucoma-related vision loss and has long been associated with an increased risk of blindness. Our understanding of the pathophysiology of ocular hypertension has significantly changed in recent decades, and new clinical evidence has allowed us to fine-tune guidelines regarding when and how to treat ocular hypertension in order to avoid vision loss.

Intraocular pressure (IOP) is the result of the dynamic process of aqueous inflow and outflow from the anterior segment of the eye [1]. In the healthy eye, the aqueous balance is fairly stable. Inflow involves a highly specialized active secretion process carried out in the ciliary body epithelium, while outflow is influenced by biochemical and mechanical factors (pressure-dependent and pressure-independent mechanisms) that facilitate drainage. Glaucoma and ocular hypertension are typically caused by a restriction in the outflow of fluid from the eye, either in the trabecular outflow apparatus (Schlemm’s canal, trabecular meshwork), the uveoscleral pathway, or the post-trabecular structures [2, 3].

Several high-quality randomized clinical trials have demonstrated that lowering IOP slows glaucoma conversion, glaucoma progression, and outcomes related to visual loss [4, 5, 6, 7, 8, 9]. However, not all eyes respond equally to the same amount of IOP elevation: most hypertensive eyes do not develop glaucoma even without treatment, and a sizeable proportion of glaucomatous eyes never register high IOPs (normal tension glaucoma) but respond well to IOP-lowering therapies [4]. These differences can be attributed to varying IOP threshold sensitivities among patients or to different mechanisms of retinal nerve fiber layer damage (vascular dysregulation, trans-lamina cribrosa pressure gradient).

Treating ocular hypertension is therefore not straightforward, and an individualized approach considering the magnitude and mechanism of intraocular pressure elevation, the daily pressure fluctuations, the presence of other risk factors (positive family history, age, low-corneal hysteresis), the patient’s risk tolerance, and the safety of available treatment options must be adopted.

2. Risk factors for ocular hypertension

Ocular hypertension (OHT) is defined when finding high-intraocular pressure readings (above 21 mmHg) in a patient without evidence of glaucomatous neuropathy. The cut-off value of “normal” IOP is based on epidemiological studies in a healthy population and is not representative of all ethnicities or age groups but serves as an accurate guideline to which all patients are compared.

The most relevant risk factors for the development of ocular hypertension are:

1. Ethnicity and age: Afro-descendants and Latinos have higher average IOPs than Caucasians. These populations also have higher prevalence of glaucoma and are considered at higher risk of glaucoma-related blindness [9]. Intraocular pressure is higher in older populations, and glaucoma prevalence rises through life in a linear fashion.

2. Family history: The presence of a first-degree relative with ocular hypertension or glaucoma increases the risk of developing ocular hypertension three to four times greater [10]. Multiple genetic loci have been identified, but inheritance is considered multifactorial with variable expressivity [11]. When there is a clear family history, hypertension tends to present itself sooner and in higher magnitude in subsequent generations.

3. Ocular pathology: Some ocular abnormalities increase the odds of developing high IOP; the most common are: pseudoexfoliation syndrome, pigment dispersion, history of active inflammation, trauma, or previous surgery [12]. Secondary OHT and glaucoma are usually approached differently from cases with no identifiable cause and management can differ. In this chapter, we will be referring almost exclusively to primary OHT and primary open-angle glaucoma (POAG).

4. Central corneal thickness and corneal hysteresis: Central corneal thickness has been found to be an independent risk factor for the development of glaucoma [7]. The theory of this association has not yet been proven but involves the relationship of corneal thickness and corneal force dampening with ocular rigidity and lamina cribrosa deformity.

Some risk factors that are frequently mentioned in literature on glaucoma and OHT can be also considered early manifestations of the disease and even be the only finding in such cases and should therefore be considered when calculating the overall risk of progression. These are:

1. Cup-to-disk ratio (CDR): A larger cup can be found in normal individuals, particularly in large discs. The cup-disk ratio is usually the first finding that alerts the clinician to look for possible glaucomatous retinal nerve fiber layer loss. In at-risk individuals, a larger CDR increases the risk of lifetime conversion to glaucoma.

2. Disc hemorrhages: also called splinter hemorrhages, are commonly found in glaucoma patients and are considered hallmark of glaucomatous progression. The finding of disc hemorrhages can weigh considerably when assessing overall risk.

3. Peripapillary atrophy: Atrophy around the optic disc is common in glaucoma and may sometimes be a predictor of RFNL thinning. Beta peripapillary atrophy is associated with higher probability of glaucoma.

3. What is the evidence on treating ocular hypertension?

3.1 Early treatment lowers the risk of glaucoma conversion in OHT

The Ocular Hypertension Treatment Study (OHTS) conducted a randomized trial with 1408 patients having ocular hypertension (defined as IOP above 24 mmHg in at least one eye) assigned to either treatment or observation [6, 7]. After a 60-month follow-up, only 4.4% of patients in the medication group and 9.5% in the observation group developed Primary Open-Angle Glaucoma (POAG), illustrating a remarkable 60% risk reduction. Over 13 years, the cumulative proportion of patients developing POAG in the treatment group was 0.16, compared to 0.22 in the observation group [6].

It is important to notice that most of the observation cohort did not develop POAG. Individual risk factors should be taken into consideration when starting medical therapy to avoid over-treatment.

3.2 Higher risk patients have greater odds for glaucoma conversion in OHT

The OHTS study also revealed that African American participants showed a higher proportion of POAG development in both groups, with 6.9% in the medication group and 12.7% in the observation group [7]. A risk factor analysis was carried out, finding that those associated with a higher risk of POAG were family history of glaucoma, corneal thickness of 555 μm or less, older age, higher IOP, and larger cup-to-disk ratio.

In the 12 year follow-up phase, early treatment was found to be more protective than delayed treatment (started after the first 7.5 years of the first stage study), particularly in the higher risk group of patients. Higher risk individuals should be approached more closely, and the decision of early treatment be considered sooner, deferring treatment in these patients may carry a penalty that may not be caught up if treatment is started only after finding glaucomatous damage.

3.3 IOP-lowering treatment slows glaucomatous progression

The Early Manifest Glaucoma Trial (EMGT) examined the efficacy of reducing IOP to prevent the progression of POAG. In this study, 255 patients with newly diagnosed POAG were randomized into two groups: a treatment group receiving laser trabeculoplasty and hypotensive drops, and an observation group. Patients in the observation group exhibited greater progression in visual fields and optic disc findings, accounting for 62% compared to 45% in the treatment group. Although both groups showed progression over time, the control group experienced more significant deterioration, suggesting the beneficial effect of treatment [8].

In established advanced glaucoma, the Advanced Glaucoma Intervention Study (AGIS) found that eyes with average IOP greater than 17.5 mmHg progressed more than those under 14 mmHg, and patients that had IOP under 18 mmHg on all visits in the 6-year follow-up had close to no change in the basal visual field defects [9].

3.4 IOP-lowering therapy slows normal tension glaucoma

IOP-lowering therapy also slows down the progression of Normal Tension Glaucoma. The Collaborative Normal Tension Glaucoma Study enrolled 140 patients and randomly assigned them to two groups [13]. One group received IOP reduction of 30% from baseline, while the other remained untreated (control group). The study found that reducing IOP by 30% slowed the rate of progression in visual fields compared to the control group. Notably, up to 65% of patients in the control group showed no progression during the 5-year follow-up.

4. Treatment strategies

Traditionally, IOP treatment starts with topical hypotensive medications, either in ocular hypertension or glaucomatous patients. These topical medications are typically the first-line approach due to their ease of use, effectiveness in lowering IOP, and relatively low risk of systemic side effects. Most glaucoma patients, and many OHT patients will use one or more topical hypotensive medication in their lifetime. Careful selection of an appropriate medication can help control the disease with great integration to the patient’s daily routines. This integration facilitates a consistent management plan, increasing the likelihood of treatment adherence and enhancing the overall efficacy of the therapeutic regimen.

Commonly prescribed topical medications include prostaglandin analogs which act enhancing uveoscleral outflow; beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors all act as aqueous production inhibitors, and rho kinase inhibitors, a newer class of hypotensive medications which act on the trabecular meshwork. Through these diverse mechanisms, they lower the IOP and halt the degeneration of retinal ganglion cells.

Recent efforts have been made to decrease medication burden and adverse effects, increase adherence, persistence, and overall patient quality of life and other patient-reported outcomes. Out of these efforts, preservative-free and fixed-combination medications have entered the market and the use of other therapies such as selective laser trabeculoplasty (SLT) and minimally invasive glaucoma surgery (MIGS) has claimed a place in the treatment of early stages of glaucoma and ocular hypertension.

This novel point of view is encapsulated in the term “interventional glaucoma,” signifying a shift in the approach toward pre-emptive tactics aimed at stalling glaucomatous progression and safeguarding vision. Central to this approach are early and safer interventions designed to strengthen adherence, amplify glaucoma control, and gauge the enhancements in quality of life. By embracing this perspective, the need for medication escalation and medication-linked adversities is decreased, while also reducing the fluctuations of intraocular pressure and the overarching trajectory of disease progression.

4.1 Medical therapy

Whenever possible, medical therapy should start with a single agent; drug combinations can be considered when a greater amount of IOP decrease is desired, and it is unlikely to be achieved with a single medication.

Prostaglandin analogues (PGAs) are usually the first choice as they have the highest potency, once-daily administration and a good safety profile [14]. There is increasing availability of preservative-free formulas worldwide. Special care should be taken in patients with history of ocular inflammation or complicated cataract surgery; otherwise, adverse effects are usually limited to mild ocular redness and discomfort. Prostaglandin orbitopathy (periorbital fat atrophy) and other cosmetic changes (hyperpigmentation) can become significant and should be assessed at every visit.

Beta-blockers are also considered a good first-line choice when PGAs are not ideal or as adjunctive therapy when treatment escalation is needed. Beta-blockers should be used with care or avoided in patients with pulmonary of cardiac problems. Other medications are usually reserved as third-line agents either alone or in fixed combinations when IOP is not at target or progression is documented. Newer drug classes such as rho-kinase inhibitors (netarsudil) and nitrous oxide donors (latanoprostene bunod) are usually used in combination with PGAs.

4.2 Selective laser trabeculoplasty (SLT)

Laser Trabeculoplasty has been utilized for glaucoma treatment for over two decades [15]. However, recent evidence from randomized controlled studies has proven its efficacy as a first-line therapy in patients with ocular hypertension (OHT) and varying degrees of glaucoma.

The LIGHT study (Laser in Glaucoma and Ocular Hypertension Treatment study) compared selective laser trabeculoplasty (SLT) to eye drops as the primary treatment. It assessed various outcomes, including quality of life, cost-effectiveness, intraocular pressure (IOP) reduction efficacy, and adverse effects. At the 36-month mark, no difference in quality-of-life scores was observed. However, there was a slight advantage in terms of the percentage of eyes reaching the target IOP, fewer treatment escalations, less progression in visual fields, and a reduced need for surgery. During the 6-year extension, 69.8% of patients in the SLT group maintained their target IOP without requiring medical treatment [16, 17].

SLT can be employed at different stages of the disease, but it exhibits a more favorable outcome profile in cases of ocular hypertension and mild primary open-angle glaucoma [16]. This approach should be considered for all patients with open-angle glaucoma or OHT in whom the decision to initiate treatment has been made. SLT can potentially defer the need for medication and mitigate associated adverse effects for a substantial portion of patients.

4.3 Glaucoma surgery

Many new surgical procedures for glaucoma management have appeared in recent years. Novel devices and techniques approaching the trabecular meshwork, the suprachoroidal space or subconjunctival filtration with improved safety profiles, quick recovery and good efficacy are now available for the treatment of early to severe glaucoma [18, 19]. These procedures are encompassed in the ever-expanding umbrella of MIGS (Minimally Invasive Glaucoma Surgery).

MIGS was initially designed for mild to moderate glaucoma, to be used in combination with cataract extraction. With widespread use and more information on results, they have been found to be effective also in more severe cases or as standalone therapy.

Trabeculectomy and glaucoma drainage devices are traditional incisional surgeries used for uncontrolled ocular hypertension and glaucoma. They are left as a secondary choice when other therapies (medication, laser, or MIGS) are insufficient or there is need for a single-digit target IOP [19]. Although they provide the lowest target IOP, postoperative complications and reinterventions are frequent, and recovery is slow. They continue to be very valuable tools for the management of refractory glaucoma and many cases of secondary glaucoma.

5. What to consider when starting treatment?

5.1 Age

The age of patients is important not only as a risk factor but also in terms of treatment considerations. When deciding on the timing and method of treatment, the patient’s life expectancy at the time of diagnosis should be carefully taken into account. While most topical medications are safe and well-tolerated and are still the first line of treatment, the prospect of undergoing treatment for decades can be discouraging.

Studies have shown that long-term use of topical treatments can lead to a decrease in conjunctival goblet cell density, reduced tear stability, and the development of ocular surface disease. Additionally, the prolonged use of prostaglandin analogs can result in cosmetic changes such as periorbital fat atrophy, iris color alteration, and eyelid pigmentation. Alpha agonists may lose some of their effectiveness due to tachyphylaxis and can even cause delayed-onset allergic conjunctivitis. It is worth noting that all hypotensive medications are associated with higher rates of cataract surgery.

When feasible, delaying the initiation of ocular hypotensive medications in younger individuals is a reasonable approach, especially in cases of low-risk ocular hypertension patients. For some patients with evident glaucomatous findings, alternative treatments like selective laser trabeculoplasty (SLT) can be used as they have demonstrated comparable efficacy without the need for a drop regimen. Trabecular minimally invasive glaucoma surgeries (MIGS) or even trabeculectomy might yield excellent long-term outcomes in cases of juvenile primary open-angle glaucoma (POAG) and considerably reduce the overall medication burden over time.

Conversely, in the case of older patients, a less aggressive approach might be considered if the glaucoma is mild and stable, if their life expectancy is shorter, or if they have significant and life-threatening systemic comorbidities. In such instances, it becomes crucial to lower intraocular pressure (IOP) sufficiently to prevent substantial vision loss within the expected lifespan. The chosen treatment should possess the best available safety, efficacy, and tolerability profile. Surgery may be preferred in cases where compliance with a drop-based therapy is difficult or unreliable.

5.2 Ocular surface disease

Ocular surface disease (OSD) is a highly prevalent ophthalmic condition. Dry eye symptoms are experienced by 8 to 30% of the general population, with an increase to 59% among glaucoma patients [20, 21, 22]. This notable increase can be attributed to the prolonged exposure to topical treatments, many of which contain benzalkonium chloride (BAK), a common preservative known to disrupt tear film balance and trigger inflammation within various ocular structures, especially the cornea [23, 24, 25, 26].

In the initiation of ocular hypotensive medications, a meticulous assessment of the ocular surface is important. This evaluation should encompass pre-existing conditions such as blepharitis, reduced tear break-up time, conjunctival and corneal epithelial defects. Additionally, it is helpful to objectively measure patient symptoms using standardized questionnaires like the Ocular Surface Disease Index (OSDI) [27]. This information helps select the best suited treatment: drop-free therapies such as SLT in patients with existent OSD or preservative-free medications and simpler, once-daily drop regimens for patients at risk.

OSD should be treated as soon as diagnosed. Eyelid margin hygiene and preservative-free lubricant drops should be prescribed to all patients with OSD and glaucoma. Ocular surface immune-modulating agents such as cyclosporine can help minimize chronic inflammatory changes to the ocular surface. Other more intensive therapies like punctual plugs, 20% autologous serum drops, or intense pulsed light should be considered if necessary.

5.3 Glaucoma severity

The amount of visual field remaining and at risk is a good surrogate measure of how intense treatment should be. Visual field loss is dependent on many mechanisms but is directly proportional to the time and magnitude of ocular hypertension. As a general rule, severe visual loss should be treated aggressively and monitored closely to avoid visual disability.

It has also been demonstrated that a target IOP in the lower teens, or even in single digits, stops progression in advanced glaucoma [9]. In these cases, it is safest to avoid IOP spikes during the day. Treatment choice should take daily fluctuations into account, considering some medications have less efficacy during the night [28].

If visual disability has occurred as a result of other ocular diseases, such as macular degeneration or diabetic retinopathy, it is also wise to have a low threshold for starting treatment when ocular hypertension is diagnosed.

5.4 Patient preference

Clear and sufficient communication is pivotal in establishing a trusting relationship between patients and their care providers. Effective communication yields positive impacts on both clinical outcomes and patient-related results. It promotes adherence to treatment regimens and cultivates realistic expectations regarding the disease. A thorough understanding of potential risks and diverse treatment options empowers patients to make informed decisions, even when those decisions involve taking calculated risks.

Risk-averse patients might opt to start medication even if their glaucoma risk is considered low. In contrast, others might feel at ease with an observation-based approach, viewing it as a means to postpone treatment and the potential complications that come with it. Equipping patients with the knowledge of what to anticipate in each scenario facilitates clinical decision-making, even when adverse outcomes do arise.

As ophthalmologists, it is crucial to provide guidance grounded in up-to-date evidence toward the most suitable choice for the patient’s specific issue. By offering an informed insight and assisting patients in navigating their options, clinicians ensure that decisions are well-informed and aligned with the individual’s needs.

5.5 Overall risk of progression

The significance of intraocular pressure (IOP) treatment lies within its integration into a comprehensive therapeutic strategy aimed at preserving visual function. Visual function encompasses vital aspects like visual acuity, depth perception, and the extent of the visual field. It holds immense importance in the overall quality of life for each individual patient. Consequently, the fixation of a target IOP only constitutes one facet of treatment. This fixation becomes adjunctive to the observation of functional or structural damage and its rate of change over time [29].

The rate of progression serves as a crucial indicator of disease dynamics. It offers insights into the speed of deterioration, the effectiveness of therapeutic interventions, and empowers clinicians to gauge the likelihood of visual impairment within specific timeframes. To compute this rate, patients need to undergo frequent visual field and structural optical coherence tomography (OCT) tests. While these tests can be cumbersome, they are necessary to establish baseline measurements, evaluate inter-test variability, and ascertain a trend of worsening.

In cases of ocular hypertension, notable thinning of the retinal nerve fiber layer (RFNL) over time might signal the earliest indication of glaucomatous neuropathy and the necessity for intervention. For patients already diagnosed with glaucoma, a faster than expected progression rate should prompt a reevaluation of the ongoing treatment plan. This could involve surgical interventions, medication escalation, and a thorough assessment of associated systemic factors or overlooked instances of intraocular pressure spikes, as well as adherence issues.

When visual function and its quantifiable parameters remain stable over time, the chosen approach, be it observation or an active treatment regimen, is likely well suited for the patient’s current condition. In such cases, ongoing monitoring can continue without needing further alterations.

6. General guidelines

6.1 Is there evidence of glaucomatous neuropathy or high risk for glaucoma development?

If the answer is yes, IOP-lowering treatment is warranted. Consider different options and comment with the patient the benefits and caveats of every approach. Evaluate the ocular surface and presence of ocular and systemic comorbidities (cataract, retinal disease, asthma, cardiac disease).

When there are no signs of glaucomatous neuropathy or high-risk factors and the patient is comfortable with an observation-only approach, educate on the importance of follow-up and continue frequent visual field and OCT testing in order to detect a worsening trend or the appearance of signs of high risk (disc hemorrhages, RFNL defects, increasing IOP).

6.2 Is there ocular surface disease?

Pre-existing OSD should be managed and added hypotensive treatments should be chosen considering the best option for both IOP management and the potential for OSD worsening. SLT should be considered the first-line treatment if possible, if additional IOP lowering is needed or SLT not possible, preservative-free and fixed combinations are the better choice.

Limiting the amount of daily drops and avoiding BAK-related toxicity can go a long way to ensure compliance to treatment and happy patients. Motivated patients are more adherent to accorded treatments. When using topical medications, it is better to start with monotherapy and adding/changing agents if target IOP is not met or adverse reactions appear.

6.3 Is there concomitant cataract?

Consider cataract surgery combined with an IOP-lowering procedure. Cataract surgery on itself has IOP-lowering effect on most patients, adding MIGS procedures/devices can lower IOP even further. Glaucoma incisional surgery can be a good choice if other options are unavailable or a larger IOP drop is needed [29].

7. Conclusions

IOP-lowering therapy should be tailored to each patient considering important risk factors (magnitude of OHT, family history, corneal thickness and hysteresis, viable visual function) and comorbidities (ocular surface disease, cataract, retinopathy), and potential problems with adherence.

Acknowledgments

I would like to thank Lucía Ximena Sadurní González MD.

Conflict of interest

The authors declare no conflict of interest.