FormalPara Key Summary Points

The intravitreal administration of treatments for diabetic macular edema can, in susceptible patients, increase intraocular pressure (IOP).

Increased IOP can threaten sight if not detected and treated promptly.

It is not possible to determine before treatment which patients will experience an IOP rise but those with a relatively high baseline IOP, a previous IOP rise, or a history of glaucoma may be more susceptible.

IOP should be monitored in all patients throughout the lifespan of their intravitreal treatment, with closer monitoring in those most at risk.

Algorithms are proposed that tailor the frequency and extent of monitoring depending on individual susceptibility and current IOP, with the aim of ensuring that any potentially problematic IOP rise is detected and treated promptly while allowing a lower level of monitoring in patients with a low risk.

Introduction

Treating diabetic macular edema (DME) often necessitates the intravitreal administration of anti-VEGF products and/or corticosteroids, either of which can increase intraocular pressure (IOP) in susceptible patients [1,2,3,4,5,6,7]. Ocular hypertension is an important risk factor for primary open-angle glaucoma and, if untreated, can lead to optic nerve damage and vision loss [8, 9]. Transient ocular hypertension is not generally considered a problem providing that the risk for glaucoma development is minimized [10], but early detection and treatment of an IOP rise are critical to ensuring that it remains transient. IOP monitoring is therefore an essential component of patient management after intravitreal therapy.

This commentary focuses on the issue of IOP monitoring after intravitreal administration of corticosteroid implants. Two such implants are approved for use in DME in Europe—a 700 μg dexamethasone implant (Ozurdex®; Allergan Ltd., Marlow, UK) that offers efficacy for up to approximately 6 months [6] and a longer-acting implant that offers continuous daily dosing of fluocinolone acetonide at 0.2 μg/day for up to 3 years (ILUVIEN®; Alimera Sciences Ltd., Aldershot, UK [7]). Some physicians also inject triamcinolone acetonide intravitreally for the treatment of DME. However, such usage is off-label in Europe, and this product is an injectable suspension rather than an implant (so provides a bolus dose rather than the slower release that is possible with an implant).

Corticosteroid-induced rises in IOP may be related to histological changes in the trabecular extracellular lamina increasing the trabecular resistance to the outflow of aqueous humour [11, 12] and possibly also trabecular fouling due to the repeated injection of silicone present in syringes and needles [13]. The development of corticosteroid-induced glaucoma may be related to environmental factors and gene locus interactions [12]. Although it is not possible to determine prior to treatment which patients will experience an IOP rise, several risk factors have been identified. These include: prior ocular hypertension or glaucoma [14,15,16,17], especially glaucoma treated with dual or triple therapy [18]; a history of an IOP rise or a prior or current need for IOP-lowering treatment [19,20,21]; a relatively high baseline IOP [14, 20, 22]; myopia [23]; axial length [24]; type 1 diabetes [18]; age [18, 24]; and Latino and South Asian ethnicity [25]. Furthermore, other factors such as implant positioning can also affect the risk post-implantation [26].

Although intravitreal corticosteroid implants are likely to be initiated by retina specialists, the potential complication of an IOP rise is an area in which glaucoma specialists have particular expertise. As a result, good communication between retina specialists and glaucoma specialists is needed for optimum patient outcomes. Guidance to assist retina specialists on the monitoring and management of IOP after intravitreal corticosteroid treatment of DME was published in 2016 [10]. This was 4 years after the first European license approval for the fluocinolone acetonide implant and at that time clinical data with this implant, and especially real-world clinical experience, were limited. Given the increase in clinical experience accumulated since then and the greater number of publications in the literature about corticosteroid implants—including, importantly, several long-term evaluations and numerous real-world evaluations (Table 1)—it is timely to revisit and update the guidance from 2016.

Table 1 Recent data on intraocular pressure (IOP) after intravitreal corticosteroid implantation (from key studies published since the guidance by Goñi et al. in 2016 [10])
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A group of six glaucoma specialists (FG, KB, JAD, MD, JGF, and AH) and two retina specialists (LK and MN) from across Europe gathered online in January and March 2021 to update the previous consensus guidance for retina specialists. Their recommendations are presented here and are designed to be suitable for implementation across Europe, subject to local adaptations in individual institutions and countries as needed. Key changes from the earlier guidance include:

  • Closer monitoring in patients who are most susceptible to developing an IOP rise (i.e., those with a baseline IOP of ≥ 22 mmHg or a prior history of an IOP event)

  • Closer monitoring in patients whose IOP increases ≥ 10 mmHg from baseline

  • Greater clarity on the timing of monitoring visits

  • Greater flexibility for retina specialists regarding when to initiate IOP-lowering medication and when to refer to a glaucoma specialist (which helps overcome logistical difficulties where local facilities are lacking)

  • Greater clarity on the stepwise introduction of treatments when IOP exceeds 25 mmHg and a de-emphasizing of the potential usefulness of selective laser trabeculoplasty as monotherapy in this scenario

  • The incorporation of a dynamic feedback mechanism which means the guidance continually adapts in line with the latest IOP measurement (to ensure it accurately reflects the current risk level throughout what could be a lengthy period of monitoring).

This article is based on previously conducted studies and does not contain any new studies performed by any of the authors.

Overview of Recent Key Data

Key data published since the previous guidance in 2016 regarding IOP and IOP-lowering treatment following intravitreal corticosteroid implantation are detailed in Table 1, and an overview of the key findings are summarized in Table 2. Overall, these recent data confirm that intravitreal corticosteroid implantation can be associated with a risk of ocular hypertension in some patients, with the risk being greater if patients have had a history of prior IOP events. In addition, the majority of IOP rises are managed with one or two IOP-lowering medications [37] (and so would generally be manageable by retina specialists), with only a small minority of eyes requiring additional medications, laser, or surgery.

Table 2 Summary of key findings from Table 1. Note that the numerous methodological differences between the analyses (especially affecting patient characteristics at baseline, treatment given, and duration of follow-up) preclude cross comparisons
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Pre-implantation Considerations

Patient selection is important for optimal efficacy and safety [39, 41]. From a safety perspective, it is critical to identify which eyes may be most susceptible to developing ocular hypertension so that their suitability for implantation can be considered carefully and their potential need for closer monitoring and additional interventions can be accommodated.

Glaucoma can be a contraindication for intravitreal corticosteroid implantation [6, 7] as it is known to increase the risk of an IOP rise [8, 18]. (In Europe, advanced glaucoma which cannot be adequately controlled by medicinal products alone is a contraindication to intravitreal dexamethasone implantation [6] and pre-existing glaucoma is a contraindication to intravitreal fluocinolone acetonide implantation [7].) Nevertheless, anecdotal reports from glaucoma specialists and the literature [11, 18, 38] show that patients with glaucoma have been successfully treated with intravitreal corticosteroid implants. Such patients could include, for example, those with glaucoma whose IOP is well controlled by medication [42] or stents and those with uveitis and glaucoma who are in great need of corticosteroid treatment and have no suitable alternatives. In such scenarios, the risk-to-benefit equation can be in favour of the need for disease control through the use of intravitreal corticosteroid treatment—although, consequent to this, there will need to be collaboration with a glaucoma specialist to ensure adequate monitoring so that risks are minimized and potential problems are detected and addressed at the earliest opportunity.

Non-glaucomatous patients who may have higher than average susceptibility to a rise in IOP include those with higher IOP at baseline or a history of a prior rise in IOP (including a history of needing IOP-lowering treatment) [19, 21]. It is logical that monitoring may need to be more frequent and/or extensive in these more susceptible patients and, as a result, we advise closer monitoring for patients with a:

  • Baseline IOP of ≥ 22 mmHg (ocular hypertension according to the European Glaucoma Society [43]).

  • History of an IOP rise to > 25 mmHg or an IOP rise of ≥ 10 mmHg.

  • Prior or current need for IOP-lowering treatment.

We recommend monitoring less susceptible patients (i.e., those without these criteria) according to the algorithm in Fig. 1 and those who have greater susceptibility (i.e., those with these criteria) according to the modified algorithm in Fig. 2.

Fig. 1
figure 1

Algorithm for monitoring and treating patients who are less susceptible to a rise in intraocular pressure (IOP) (i.e., patients with a baseline IOP of < 22 mmHg and no prior history of an IOP event). Guidance depends on whether the latest IOP measurement classifies patients as low risk, medium risk, or high risk for developing a potentially concerning IOP rise

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Fig. 2
figure 2

Algorithm for monitoring and treating patients who may be more susceptible to a rise in intraocular pressure (IOP) (i.e., patients with a baseline IOP of ≥ 22 mmHg or a prior history of an IOP event). Guidance depends on whether the latest IOP measurement classifies patients as medium risk or high risk for developing a potentially concerning IOP rise

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Post-Implantation Recommendations

IOP should be checked within the first week after implantation [7]. Figure 1 shows that the latest IOP reading and the degree of change in IOP from baseline are used to classify whether a patient has a low, medium, or high risk of developing a potentially concerning IOP rise. The algorithm in Fig. 2 omits the lower risk classifications because patients following this algorithm have inherent risk factors that could remain for the lifetime of any implant—so their monitoring needs to retain a consistently higher level of alertness.

Each risk category is associated with different monitoring and/or treatment recommendations in line with the level of surveillance and intervention that is appropriate (Figs. 1, 2, 3). With each subsequent IOP check, the level of risk is re-evaluated based on the latest IOP level. Therefore, if a patient’s IOP rises and falls during the post-implantation follow-up, then the patient’s risk category may also rise and fall—triggering adaptations to monitoring and/or treatment as necessary. In this way, the algorithms offer a dynamic reflection of a changing clinical situation (Fig. 3).

Fig. 3
figure 3

Clarification of intraocular pressure (IOP) monitoring requirements in the different risk groups depicted in the algorithms of Figs. 1 and 2. Patients may move between the different risk groups at any time during monitoring depending on their latest IOP

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Both algorithms recommend assessing IOP at 2–7 days after implantation [7], 1 month after implantation, and 2 or 3 months after implantation. Thereafter, the frequency of subsequent monitoring depends on the risk category (every 3 months in the low-risk category, at the retina specialist’s discretion in the medium-risk category, and at the glaucoma specialist’s discretion in the high-risk category). The 1-month check has been shown to have value in identifying an increased risk for subsequent ocular hypertension [24] but an increase in IOP can occur at any time during the life of the implant and not only in the weeks and months immediately following implantation. Indeed, with the fluocinolone acetonide implant, it has been reported that the first observation of an IOP > 25 mmHg occurred a mean (± SD) of 418 ± 324 days post-implantation [19]. This wide variability in possible timing underscores the need for regular monitoring throughout the lifespan of the implant. It is similarly important to maintain monitoring throughout the total duration of treatment with repeated dexamethasone implants because, at least in patients with uveitis or retinal vein occlusion, a need for glaucoma surgery has been reported to have arisen after anywhere from one to ten implants—thus, it cannot be assumed that a lack of IOP rise early in treatment precludes the risk of a rise occurring later [8].

Both algorithms show that all patients in the medium- or high-risk groups should have their visual field recorded at least once. This is good clinical practice and important for legal defence reasons, so is valuable even if it is non-contributory.

Imaging of the optic head and/or retinal nerve fibre layer is also advised as soon as a patient is classified as medium or high risk. In the medium-risk group, it should be repeated every 3 months if IOP increases (i.e., is unstable) or every 6 months if IOP has not increased (i.e., is stable). In the high-risk group, it should be monitored every 3 months.

Regarding treatment, in the low-risk group no IOP-lowering treatment is necessary if the IOP remains < 22 mmHg but IOP monitoring should continue at least quarterly for the life of the implant. In the medium-risk group, IOP-lowering treatment may be advised at the discretion of the retina specialist or glaucoma specialist. In the high-risk group, IOP-lowering treatment is usually necessary—initially one treatment and, if this is not sufficiently effective within 1–2 weeks, then two treatments. If these fail to maintain the IOP < 25 mmHg within another 1–2 weeks, the patient should be referred to a glaucoma specialist.

The results of a recent study evaluating referrals to glaucoma specialists from optometric practitioners that were based on IOP alone suggest that limiting referrals to patients who are at least 45 years of age (in addition to having an IOP of at least 25 mmHg) may improve the effectiveness of referrals without missing any patients who have glaucoma or who require IOP-lowering treatment [44]. Currently, we do not know if this might also be the case with referrals from retina specialists.

Hypothetical Patient Scenarios Illustrating the Guidelines in Action

JOHN

 

History

No prior history of intravitreal corticosteroid treatment or raised IOP or glaucoma

Baseline IOP

14 mmHg

Pre-implantation assessment

John does not have any of the above-mentioned factors that might make him more susceptible to an IOP rise and so his retina specialist can consider him for an intravitreal corticosteroid implant without needing to consult glaucoma colleagues

Post-implantation monitoring

John is treated with the intravitreal corticosteroid implant. As he does not have any of the key factors increasing his susceptibility to an IOP rise, his monitoring follows the algorithm for less susceptible patients (Fig. 1). His IOP monitoring starts on the standard schedule (i.e., 2–7 days, 1 month, and 2–3 months after implantation and, thereafter, depending on the relevant risk classification) as follows:

 

7 days post-implantation:

IOP is 19 mmHg, so he is in the low-risk group

 

1 month post-implantation:

IOP is 24 mmHg and, because this is ≥ 10 mmHg higher than his baseline IOP, he moves to the high-risk group. His visual field is recorded, imaging is performed, and he is treated with one topical IOP-lowering medication within 1–2 weeks. He is followed up again 1–2 weeks after starting the medication

 

1.5 months post-implantation:

IOP is 26 mmHg, so a second topical IOP-lowering medication is added to his treatment

 

2 months post-implantation:

IOP is still 26 mmHg, so he is referred to a glaucoma specialist

WILLIAM

 

History

No prior history of intravitreal corticosteroid treatment or raised IOP or glaucoma

Baseline IOP

21 mmHg

Pre-implantation assessment

William does not have any of the above-mentioned factors that might make him more susceptible to an IOP rise and so his retina specialist can consider him for an intravitreal corticosteroid implant without needing to consult glaucoma colleagues

Post-implantation monitoring

William is treated with an intravitreal fluocinolone acetonide implant. As he does not have any of the key factors that could increase his susceptibility to an IOP rise, his monitoring follows the algorithm for less susceptible patients (Fig. 1). His IOP monitoring starts on the standard schedule (i.e., 2–7 days, 1 month, and 2–3 months after implantation and, thereafter, depending on the relevant risk classification) as follows:

 

5 days post-implantation:

IOP remains at 21 mmHg, so he remains in the low-risk group

 

1 month post-implantation:

IOP is 22 mmHg, so he moves to the medium-risk group and has his visual field recorded and imaging performed for the first time

 

2 months post-implantation:

IOP returns to baseline level of 21 mmHg, so he returns to the low-risk group and his next IOP check will be in 3 months

 

5 months post-implantation:

IOP is 21 mmHg, so he remains in the low-risk group and continues with IOP checks quarterly

 

8 months post-implantation:

IOP is 20 mmHg

 

11 months post-implantation:

IOP is 28 mmHg, so he moves to the high-risk group, is treated within 2 weeks with a single topical IOP-lowering drug and, as he has not had his visual field recorded and imaging performed within the last 3 months, these are repeated. His next IOP check is scheduled for 2 weeks after starting the medication

 

12 months post-implantation:

IOP is 22 mmHg, so he moves to the medium-risk group and continues the medication. His retina specialist decides to schedule the next IOP check for 4 weeks later

 

13 months post-implantation:

IOP is 21 mmHg, so has returned to the baseline level. He returns to the low-risk group and continues the medication. His IOP continues to be monitored every 3 months for the 36-month lifespan of the fluocinolone acetonide implant

 

16 months post-implantation:

IOP is 21 mmHg

 

19 months post-implantation:

IOP is 21 mmHg. In this low-risk scenario, a washout of the topical medication can be considered to determine whether or not the medication needs to be continued

 

22 months post-implantation:

IOP is 21 mmHg

 

25 months post-implantation:

IOP is 21 mmHg

 

28 months post-implantation:

IOP is 20 mmHg

 

31 months post-implantation:

IOP is 20 mmHg

 

34 months post-implantation:

IOP is 21 mmHg

ANN

 

History

Ann hates injections but is very motivated to do everything possible to protect her eyesight. She once had an IOP of 28 mmHg a few weeks after a previous intravitreal dexamethasone implant but this was controlled with a single glaucoma medication

Baseline IOP

20 mmHg

Pre-implantation assessment

Because of her prior history of an IOP rise beyond 25 mmHg after intravitreal corticosteroid treatment, Ann is more susceptible than most patients to developing another rise in IOP. As a result, her retina specialist should discuss protocols with the local glaucoma team to help determine Ann’s potential suitability for an intravitreal corticosteroid implant. The glaucoma team can also advise on monitoring and a plan of action if she has another rise in IOP

Post-implantation monitoring

Ann receives a fluocinolone acetonide implant because she can only tolerate the thought of a single injection every 3 years and not more frequently. Because of her prior history of an IOP event, her monitoring starts by following the algorithm for more susceptible patients (Fig. 2). Her visual field is recorded and imaging is performed. Her IOP monitoring starts on the standard schedule (i.e., 2–7 days, 1 month, and 2–3 months after implantation and, thereafter, depending on the relevant risk classification) as follows:

 

5 days post-implantation:

IOP is 20 mmHg, so she is in the medium-risk group

 

1 month post-implantation:

IOP is 21 mmHg, so she stays in the medium-risk group

 

3 months post-implantation:

IOP is 27 mmHg, so she moves to the high-risk group and within 1–2 weeks is treated with a single IOP-lowering medication. Her visual field and imaging are repeated and her IOP is scheduled for review within 1–2 weeks of starting treatment

 

3.5 months post-implantation:

IOP is 25 mmHg, so she moves back to the medium-risk group. Her retina specialist schedules her next IOP check for 4 weeks later

 

4.5 months post-implantation:

IOP remains at 25 mmHg and her retina specialist adds a second topical IOP-lowering medication to reduce IOP further and schedules another IOP check for 6 weeks later

 

6 months post-implantation:

IOP is 25 mmHg. Ann continues with the medication and stays in the medium-risk group. Her retina specialist decides to continue monitoring IOP every 2 months. Because IOP has not increased over the last two visits, visual field and imaging only need to be repeated within 6 months of the last check (which was at 3 months post-implantation), so these are scheduled for the next visit

 

8 months post-implantation:

IOP is 22 mmHg, visual field and imaging are repeated

 

10 months post-implantation:

IOP is 22 mmHg

 

12 months post-implantation

IOP is 21 mmHg

 

14 months post-implantation:

IOP is 21 mmHg, visual field and imaging are repeated

 

16 months post-implantation:

IOP is 21 mmHg

 

18 months post-implantation:

IOP is 21 mmHg

 

20 months post-implantation:

IOP is 21 mmHg, visual field and imaging are repeated. Her retina specialist has concerns over a possible change in the retinal nerve fibre layer so refers Ann to a glaucoma specialist

ELSIE

 

History

Elsie has no prior exposure to intravitreal corticosteroids but has been on IOP-lowering medication for several months

Baseline IOP

19 mmHg

Pre-implantation assessment

Because of her existing need for IOP-lowering medication, Elsie is more susceptible than most patients to experiencing a corticosteroid-induced rise in IOP. Her retina specialist should discuss protocols with the local glaucoma team to help determine the potential suitability of an intravitreal corticosteroid implant. The glaucoma team can also advise on monitoring and a plan of action should a further rise in IOP occur

Post-implantation monitoring

Elsie receives an intravitreal corticosteroid implant and, because she is already on IOP-lowering treatment, her monitoring starts by following the algorithm for more susceptible patients (Fig. 2). Her visual field is recorded and imaging is performed. Her IOP monitoring starts on the standard schedule (i.e., 2–7 days, 1 month, and 2–3 months after implantation and, thereafter, depending on the relevant risk classification) as follows:

 

7 days post-implantation:

IOP is 19 mmHg, so she is in the medium-risk group

 

1 month post-implantation:

IOP is 21 mmHg, so she remains in the medium-risk group. As her IOP values over the last 2 visits have been unstable (i.e., have increased), her visual field and imaging are flagged to be repeated every 3 months and the results are to be shared with a glaucoma specialist

 

3 months post-implantation:

IOP is 22 mmHg and, as indicated previously, visual field and imaging results are repeated and the results shared with a glaucoma specialist for advice on ongoing management