Improving the paediatric eye examination can be achieved with several small steps, according to Mr Jeff Locke, a past co-president of the Canadian Orthoptic Society. Mr Locke is an orthoptist/instructor and team lead in the visual electrophysiology lab at IWK Health in Halifax, Nova Scotia, Canada.

“We can streamline things and make the examination 1% better by being more competent in assessing visual acuity, checking for binocular single vision, and knowing what visual electrophysiology can do in this age group,” he said.

For vision to be normal, stimuli need to get through our optics to the retina, for the retina to relay to the optic nerve and for the optic nerve to relay to the cortex. “Acuity can be based on what aspects of the pathway are stimulated,” Mr Locke explained.

To benchmark 20/20 vision in an infant, the testing types and acuity being measured need to be altered. “We need to shift to more detection-based acuity versus recognition,” he said. In pre-verbal children, forced-choice preferential looking (FPL) tests such as Cardiff and Teller are not the most accurate in detecting and managing amblyopia, he pointed out. He noted that it is easy to become complacent with FPL tests and stop documenting those earlier learned tests.

As a child reaches more visual milestones as they age from newborn to 1 year, the physician can perform more complex testing. “It does not mean that those tests administered during earlier milestones [when a child was younger] are no longer useful,” he explained. “They can add great qualitative aspects to your vision examination.”

Indeed, vision testing in infants needs to have qualitative more than quantitative assessments, Mr Locke explained. A quantitative test such as the FPL test serves as a benchmark for normal vision in infants and provides a value over time, he noted. That said, qualitative tests are quick to perform and can aid in detecting asymmetry in vision, he added.

In terms of vision assessment tests, Mr Locke pointed to research which concluded that optokinetic nystagmus induction methods have been found to be suboptimal in determining visual acuity thresholds. He noted, however, that they can be a great qualitative indicator of the visual pathway since intact pursuit and saccadic centres are needed, as is normal cranial nerve innervation to the extra-ocular muscles.

Mr Locke pointed out that more recent research

 has suggested a strategy for a paediatric visual acuity examination. “[The study authors] advised for best compliance to start with binocular visual acuity with Cardiff at 50 cm, followed by induced tropia,” he said.

“Once these are successfully completed, you can then try monocular visual acuity at 50 cm with your FPL Cardiff [test]. Their view was that assessing both FPL Cardiff at 50 cm and induced tropia allows for more accurate visual assessment and allows practitioners to obtain more information should they lose cooperation [from the paediatric patient].

An educated assumption is being made based on observational data and detection-based acuity with paediatric examinations, Mr Locke explained. “When trying to make a comparison between detection type of acuities, like with forced-choice preferential looking, we are likely overestimating acuity, and it becomes challenging to detect mild to moderate levels of amblyopia,” he said.

“Each detection type of acuity has shown validity in assessing the paediatric population, but the sensitivity in detecting amblyopia is variable among tests. None appear to be as robust as crowding-based testing.”

The goal needs to be to maximise the visual examination by combining multiple methods of detection-based testing, not only to increase the sensitivity but also to gain more general knowledge of the paediatric patient’s ocular health, Mr Locke said. “Do as much as you can binocularly [assessment] while the child is getting comfortable with you, but at the same time, you are extracting data.”

Mr Locke stressed that the FPL test outcome should not be the only endpoint in a paediatric vision assessment. “Make your exam 1% better by adding a qualitative measurement into the mix,” he said. And for those who do not use the FPL test, Mr Locke advised setting a grading standard across the clinic for fixation testing to help follow amblyopia over time, noting that children do not need to be old enough to respond verbally before binocularity is assessed.

There are, however, some objective methods being employed to provide a sense of binocularity. “We can test motor fusion capability in infants, and newer investigations in the use of the FPL test in stereopsis are emerging,” he said. Detecting stereopsis will help to guide a care plan and add confidence to the visual acuity assessment, Mr Locke noted.

He said that the challenge with visual electrophysiology in paediatrics is that most of the tests require an infant or toddler who is being assessed to cooperate for accurate results to be obtained; this means the tests are not always practical, with the exception of the electroretinogram (ERG), which can be done under sedation.

“The ERG is our bread and butter, but they cannot localise dysfunction specifically to the macula,” he said. Visually evoked potentials (VEPs) offer an objective measurement at the cortex, but anomalies at any level of the optic pathway (optics, macula, optic nerve, optic pathway) can result in VEP pathology, he noted.

Another clinical pearl that Mr Locke offered is that assessors should avoid having their backs turned to their paediatric patients. He suggested placing the computer screen where information is being inputted in such a way as to maintain a line of sight to the child being assessed.

This article is based on a presentation at the virtual 31st annual Jack Crawford Day paediatric ophthalmology update. Mr Locke has no financial disclosures related to this content.

1. Kutschke PJ. Preverbal assessment for amblyopia. Am Orthopt J. 2005;55:53-61.

2. Nanda KD, Blaha B, Churchfield WT, et al. Induced tropia test and visual acuity testing in nonverbal children. J Binocul Vis Ocul Motil. 2018;68:134-136.

Articles

New strategies are considered for obtaining information from visual assessments while ensuring compliance from paediatric patients.

Finding ways to finesse eye examinations in paediatric patients

Extensive preclinical data show that inhibition of the protein angiopoietin-2 (Ang-2) can lead to reduced endothelial barrier breakdown, vascular leakage, inflammatory responses and neovascularisation, as well as increased pericyte coverage.

 An investigational bispecific antibody, faricimab (Roche), works by neutralising Ang-2 and vascular endothelial growth factor A (VEGF-A) via simultaneous and independent binding. This dual approach might offer benefits beyond anti-VEGF monotherapy in the management of chronic retinal disease.

Primary 1-year results from global Phase 3 comparator-controlled trials investigating faricimab in diabetic macular oedema (DMO) and neovascular age-related macular degeneration (nAMD) were presented during Bascom Palmer Eye Institute’s Angiogenesis, Exudation, and Degeneration 2021 Meeting in February and further reviewed in presentations at The Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting.

The drug candidate demonstrated sustained efficacy and the potential for extended durability, with the majority of participants on treatment intervals of at least every 12 weeks at 1 year (Table 1).

 The studies supporting these findings are discussed as follows.

The YOSEMITE and RHINE DMO trials, enrolling 1,891 participants across 353 study sites, met the primary endpoint for vision change from baseline at 1 year. Gains in best-corrected visual acuity (BCVA) from baseline (averaged over Weeks 48, 52 and 56) with faricimab 6 mg, dosed every 8 weeks (Q8W) after four monthly loading doses—or personalised treatment interval (PTI) up to every 16 weeks (Q16W) after six loading doses—were non-inferior to aflibercept (Eylea, Regeneron) 2 mg administered Q8W after five loading doses in patients with DMO.

Although neither faricimab treatment arm demonstrated superiority over aflibercept for vision change, improved anatomic outcomes were observed. Change in central subfield thickness (CST) from baseline consistently favoured faricimab, and more faricimab-treated patients achieved absence of both DMO and intraretinal fluid. Rates of absence of subretinal fluid were high and comparable between faricimab and aflibercept, and the proportion of patients showing improvement in diabetic retinopathy severity was similar across treatments.

Patients in the faricimab PTI arm were treated using a standardised objective regimen based on the treat-and-extend concept, with dosing interval adjusted (4-week increments up to a maximum of 16 weeks) based on treatment response as measured by CST and BCVA. In the faricimab PTI arm, 72% were on quarterly or longer dosing intervals, with 52% on 4-monthly dosing intervals, at Week 52. Across both Phase 3 studies throughout Year 1, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and the potential for extended dosing using the PTI algorithm.

TENAYA and LUCERNE are global Phase 3 studies evaluating the efficacy and safety of faricimab dosed up to Q16W after four initial monthly doses compared with aflibercept given Q8W after three monthly loading doses in 1,329 treatment-naive patients with choroidal neovascularisation secondary to AMD. The trials are taking place across 271 sites worldwide.

The studies have two treatment arms: faricimab 6 mg given at fixed intervals of every 8, 12 or 16 weeks after four monthly loading doses, based on disease activity assessment (BCVA and CST criteria as well as investigator’s evaluation) at Weeks 20 and 24, and aflibercept 2 mg given at fixed Q8W intervals after three initial monthly doses (Table 2).7 After assignment to the respective treatment interval group, no subsequent interval adjustments nor rescue injections were permitted.

The faricimab treatment protocol was informed by results from the Phase 2 STAIRWAY clinical trial for nAMD, where 65% of faricimab-treated patients had no disease activity 12 weeks after the last loading dose.8 Vision gains were fully maintained up until Week 52 with faricimab dosed up to Q16W and Q12W and were comparable to monthly ranibizumab, suggesting extended disease stability after faricimab treatment.

In TENAYA and LUCERNE, mean gains in BCVA from baseline for faricimab dosed up to Q16W were non-inferior to aflibercept Q8W in patients with nAMD at 1 year, averaged over Weeks 40, 44 and 48: +5.8 letters versus +5.1 letters respectively in TENAYA and +6.6 letters for both treatments in LUCERNE. A comparable proportion of patients gained or maintained vision with faricimab and aflibercept, with meaningful and comparable reductions in CST from baseline until Week 48.

The proportion of faricimab patients on at least Q12W dosing intervals was 79% and the proportion on Q16W dosing intervals was 45% during the first year. The median number of injections was six with faricimab and eight with aflibercept.

Vitreo-retinal specialist Dr Arshad M. Khanani commented: “For me, the biggest unmet need in patients with nAMD is durability. Data from numerous studies reveal that patients with nAMD are not receiving the injections they need in the real world, with undertreatment and inferior vision outcomes compared with clinical trials.”

He added: “Data from the global Phase 3 trials of faricimab in nAMD demonstrate better durability than the current available anti-VEGF agents, with eight out of ten patients achieving sustained vision gains on quarterly or longer treatment intervals and with a well-tolerated safety profile. This is great news for physicians and patients that we may have a more durable option in the future to decrease treatment burden for patients with nAMD.”

Future long-term outcome data, including second-year results from the faricimab Phase 3 programme and the planned 2-year extension studies, will provide additional important insights into better understanding the benefits of dual Ang-2/VEGF inhibition and resulting vascular stability.

1. Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. 

2. Joussen AM, Ricci F, Paris LP, et al. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. 

3. Wykoff CC, Abreu F, Basu K, et al. Faricimab in diabetic macular edema (DME): YOSEMITE and RHINE study results. Presentated at: Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration. 12–13 February 2021; virtual.

4. Heier JS, Basu K, Ives J, et al. Faricimab in neovascular age-related macular degeneration: TENAYA and LUCERNE study results. Presentated at: Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration. 12–13 February 2021; virtual.

5. Wells JA, Wykoff CC, Willis JR, et al. Efficacy, durability, and safety of faricimab in diabetic macular edema (DME): one-year results from the phase 3 YOSEMITE and RHINE trials. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.

6. Khanani AM, Heier J, Ruiz CQ, et al. Faricimab in neovascular age-related macular degeneration: 1-year efficacy, safety, and durability in the phase 3 TENAYA and LUCERNE trials. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.

7. Guymer RH, Ruiz CQ, Willis JR, et al. Dual angiopoietin-2 and VEGF-A inhibition with faricimab in neovascular age-related macular degeneration: phase 3 TENAYA and LUCERNE trial design. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.

8. Khanani AM, Patel SS, Ferrone PJ, et al. Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: the STAIRWAY phase 2 randomized clinical trial. 

Results from Phase 3 trials of bispecific antibody faricimab demonstrate that it is more durable than currently available agents, and it has a good safety profile. 

Investigative antibody shows sustained efficacy in retinal disease studies

While investigators have found little difference in visual outcomes and complications between IOL replacement and rescue for sutureless intrascleral fixation of dislocated IOLs, the choice remains debatable. As a result, surgeons must determine which option is likely to provide the best outcome for a patient.

IOLs become dislocated in approximately 0.2–2% of cases after cataract surgery, and the possible treatments for dislocated posterior-chamber IOLs include open-loop anterior-chamber IOLs and iris- and scleral-sutured posterior-chamber IOLs. These techniques have similar outcomes, explained Dr Jingyi Ma, from the Faculty of Medicine and Dentistry at the University of Alberta in Canada.

IOL rescue is a possibility in eyes in which scleral fixation is performed as a secondary procedure. However, there is not enough information about IOL rescue to ascertain the long-term visual and surgical outcomes compared with IOL replacement.

Dr Ma and colleagues carried out a retrospective cohort study from January 2014 to January 2017 that included patients (136 eyes) with a dislocated posterior-chamber IOL who were treated with secondary sutureless intrascleral tunnel fixation of the dislocated IOL. The procedures were performed by one of five vitreoretinal surgeons at the Royal Alexandra Hospital in Edmonton, Alberta, Canada.

The pre-existing IOL was either used again or replaced with a three-piece IOL.As Dr Ma explained, the study outcomes were the postoperative best-corrected visual acuity (VA) at 2 and 6 months, the need for anti-inflammatory drops postoperatively, complications, and indications for another surgery at 2 and 6 months.

Thirty-nine patients underwent IOL rescue and 97 had IOL replacement procedures. The mean patient age in those who underwent IOL rescue or replacement was 68.9 and 71.8 years, respectively. The respective follow-up times were 13.6 and 12.3 months. Dr Ma reported that the two groups were balanced for gender, VA and the duration of the pre-existing IOL.

Regarding VA, the IOL rescue group fared slightly better at 6 months postoperatively, than the IOL replacement group, compared with baseline. Anti-inflammatory drops were used less often in both groups at 2 and 6 months.

“At 6 months, 13% of the IOL rescue group needed drops compared with 19% in the IOL replacement group, although the difference did not reach significance,” Dr Ma said. At 6 months, 12 complications developed in the IOL rescue group and 31 in the IOL replacement group, reflecting complication rates of 31% and 32%, respectively. The most frequent were cystoid macular oedema in three and eight eyes, inflammation in three and seven eyes, and elevated intraocular pressure in two and six eyes, respectively.

A subsequent surgery was required in 26% and 13% of the IOL rescue and replacement groups, respectively. The mean times to the first surgery were 1.6 and 2.1 months.

Survival analysis showed that if another surgery was required, the need arose within the first few months of the initial surgery. After this, both groups remained stable. The risk factors identified for a subsequent surgery were the presence of a complication (hazard ratio [HR], 2.8) and worse VA at 2 months (HR, 1.5). Lens replacement had a lower, non-significant HR for failure.

IOL rescue may provide a slight benefit because of the better postoperative VA and less need for use of anti-inflammatory drops. However, IOL replacement is generally associated with fewer instances of a second surgery being required, which approached significant levels.

The risk factors for a subsequent surgery are complications and worse VA at 2 months, Dr Ma said. “Both IOL replacement and rescue are reasonable options for the sutureless scleral fixation technique,” she concluded.

This article is adapted from Dr Ma’s presentation at the American Academy of Ophthalmology’s recent virtual annual meeting. She reported no financial interest in this subject matter.

There is no significant difference between IOL replacement and rescue in terms of postoperative visual and surgical outcomes for eyes undergoing secondary IOL scleral fixation.

IOL replacement vs rescue: The ophthalmologist's dilemma

Non-exudative macular neovascularisation (MNV) is asymptomatic, but it is important to identify MNV lesions because they seem to be a precursor for the development of exudative disease, according to Dr Philip J. Rosenfeld, professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida, United States. Treatment-naive MNV is now recognised as a state of age-related macular degeneration (AMD) that can be accurately detected with swept-source optical coherence tomography angiography (SS-OCTA).

Dr Rosenfeld discussed the detection, natural history and management of treatment-naive MNV in a presentation at the 2021 Ohio Ophthalmological Society virtual annual meeting. “A double-layer sign (DLS) or shallow, irregular retinal pigment epithelial elevation (SIRE) on the structural OCT B-scan is a characteristic feature of these lesions,” said Dr Rosenfeld.

“Finding these lesions in eyes with dry AMD is important because they have a high risk of conversion to exudative AMD. So far, we have not been able to predict which eyes are likely to progress to exudation based on anatomic changes. Therefore, close follow-up and at-home monitoring [are] crucial in these patients to prevent vision loss.”

Dr Rosenfeld highlighted his message about monitoring with a case history involving a patient who presented in January 2020 with large drusen and 20/40 visual acuity (VA). Routine SS-OCT showed structural elevation of the retinal pigment epithelium (RPE) consistent with drusen in the right eye, but no evidence of exudation.

Non-exudative MNV was detected with SS-OCTA imaging, where the areas of confluent drusen corresponded to a DLS seen on individual B-scans. Segmentation of RPE-Bruch’s membrane on the SS-OCTA angiographic flow map showed that the patient had three independent neovascular complexes.

The patient was counselled to return for follow-up in March 2020, but because of the COVID-19 pandemic, she cancelled that appointment. A re-scheduled visit in April was also cancelled. In May, 4 months after her January appointment, she presented to the emergency department because of sudden vision loss in the right eye.

Examination showed count fingers VA and identified a massive sub-macular haemorrhage along with exudation. “This situation could have been prevented by home monitoring and even better by home OCT monitoring that could have showed exudation developing long before the haemorrhage occurred,” Dr Rosenfeld said.

Dr Rosenfeld credited the ability to detect MNV to Dr Ruikang Wang of the University of Washington in Seattle, United States, who developed an optical microangiography algorithm that enables flow detection in OCT images. Using specific segmentation strategies, clinicians can identify subclinical MNV lesions using a number of different slab configurations with different boundaries.

For the purposes of his study, Dr Rosenfeld used a slab extending from the outer retina (OR) to the choriocapillaris (CC), which is termed the ORCC slab. He noted that the presence of subclinical MNV had been described in the 1990s in eyes that had undergone indocyanine green angiography (ICGA). The ability to identify these lesions equally well using non-invasive SS-OCTA imaging was demonstrated by Dr Rosenfeld and his colleagues in a study of patients with asymptomatic, intermediate AMD in one eye and exudative NV AMD in the fellow eye.

Subsequently, Dr Rosenfeld and his colleagues went on to investigate the prevalence and natural history of non-exudative MNV in dry AMD. For this study, they included patients with dry AMD in one eye and a fellow eye with exudative AMD. In the eyes with dry AMD, they found a 14-fold increased risk of developing exudation within 2 years among eyes with non-exudative MNV compared with eyes that did not have subclinical MNV.

Overall, if the fellow eye had exudative AMD, the prevalence of a non-exudative MNV in an eye with dry AMD was 13%. The prevalence was similar in eyes with either intermediate AMD or geographic atrophy.

Follow-up of eyes with non-exudative MNV showed that the lesions can grow without becoming exudative. Anti-vascular endothelial growth factor (VEGF) treatment was administered when symptomatic fluid developed in association with a decrease in vision; the treatment was effective in resolving the fluid and improving VA, but there were no obvious effects on lesion morphology for type 1 MNV, which comprised 93% of the lesions.

Search for changes that predict exudation

Studies conducted to find possible biomarkers to predict exudative conversion have so far shown no association with size or growth of the MNV prior to exudation or with changes in the volume of pigment epithelial detachments associated with the MNV prior to exudation, choriocapillaris flow deficits or the surrounding choroidal vasculature.

 “Additional potential predictors we are looking at include flow velocity within the MNV or in the choriocapillaris around the MNV and changes in choroidal blood flow,” Dr Rosenfeld noted.

He explained that in the Phase 2 FILLY study investigating pegcetacoplan for the treatment of geographic atrophy, the adverse event analysis showed that new-onset exudation developed in a dose-dependent fashion, occurring in 21% of eyes treated monthly with the investigational agent, in 9% of eyes receiving treatment every other month, and in only one eye (1.2%) in the sham-treated control group.

 A post hoc review of images obtained at baseline showed that the DLS was present in 73% of eyes that developed exudative AMD versus 32% that did not develop exudation.

“These eyes with the DLS had subclinical neovascularisation, but we were not prepared to capture these eyes at baseline,” Dr Rosenfeld explained. “Now, in the Phase 3 trials investigating pegcetacoplan, DLS at baseline is being identified and these eyes are being followed carefully for the development of exudation that will be treated with anti-VEGF therapy.”

However, Dr Rosenfeld added that the take-home message from FILLY “is that the VA outcome was just as good in eyes that developed exudation compared with those that did not because they were treated promptly with, and responded very well to, anti-VEGF therapy.”

This article is based on Dr Rosenfeld’s presentation at the 2021 Ohio Ophthalmological Society virtual annual meeting. Dr Rosenfeld receives research support from and is a consultant to Carl Zeiss Meditec and is chairman of the steering committee of the Advanced Retina Imaging Network, which is a global consortium of clinical researchers and the Zeiss Medical Technology business group.

1. Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. 

2. Yang J, Zhang Q, Motulsky EH, et al. Two-year risk of exudation in eyes with nonexudative age-related macular degeneration and subclinical neovascularization detected with swept source optical coherence tomography angiography. 

3. Shen M, Zhang Q, Yang J, et al. Swept-source oct angiographic characteristics of treatment-naive nonexudative macular neovascularization in amd prior to exudation. 

4. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. 

5. Wykoff CC, Rosenfeld PJ, Waheed NK, et al. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. 

Swept-source optical coherence tomography angiography can detect eyes at risk of developing exudative disease.

Swept-source OCT angiography aids detection of dry AMD

Mitigating inflammation after cataract surgery has always been critical, but heightened expectations among today’s refractive cataract surgery patients reinforce that imperative. Despite steady advances in surgical techniques, postoperative inflammation, if uncontrolled, may result in discomfort, delayed recovery and reduced visual outcomes.

Although topical corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been the historical standard for inflammation control following ocular surgery, the likelihood of inconsistent patient adherence to these medications is high, and this behaviour is associated with compromised outcomes.

The need for targeted anti-inflammatory treatments that minimise the challenges associated with topical dosing and patient adherence has given rise to innovative drug delivery systems, such as dexamethasone intraocular suspension 9% (Dexycu, EyePoint Pharmaceuticals), the first single-dose, sustained-release intraocular corticosteroid approved by the United States Food and Drug Administration (FDA) for inflammation following ocular surgery.

This liquid suspension is injected at the end of ocular surgery using a standard 27-gauge cannula; after an immediate bolus, the approximately 2-mm spherule delivers a tapering dose of dexamethasone to control inflammation through the first postoperative month.

Impressive Phase 3 clinical study outcomes influenced my initial decision to offer the dexamethasone intraocular suspension 9% option to my patients.

 In one Phase 3, randomly assigned, double-masked, placebo-controlled trial, significantly more of the treated eyes (66%) had anterior chamber cell clearing at postoperative Day 8, versus 25% of those given placebo (vehicle injection).

In another Phase 3, open-label safety study, dexamethasone intraocular suspension 9% was found to be comparable to four-times-daily topical prednisolone drops.

 The most common adverse events were increased intraocular pressure (IOP; 11.1%), iritis (6.3%) and systemic effects (7.9%, dexamethasone intraocular suspension 9% group; 10.9%, prednisolone group). Among the patients receiving the dexamethasone suspension, 68.7% strongly agreed that not having to use eye drops was very convenient.

Further evidence validating my use of this intraocular delivery method has emerged from a multicentre retrospective study of the real-world performance of dexamethasone intraocular suspension 9%.

 The investigators aimed to characterise surgeons’ early experiences with dexamethasone intraocular suspension 9% using data from a large number of patients and study sites.

Data were collected from records of 641 eyes of 527 patients who received the agent at the end of cataract surgery between March and December 2019, the months immediately following the drug’s becoming available on the market. In this retrospective study, among those eyes with a recorded value at each time point, complete anterior chamber cell clearing was observed in 40%, 65%, 85% and 90% at postoperative Days 1, 8, 14 and 30, respectively.

Targeted best corrected visual acuity was achieved in 97% of eyes. Mean IOP at postoperative Day 1 was 18.6 mm Hg, with levels decreasing through to postoperative Day 30.

These real-world data from multiple US study centres demonstrate the anti-inflammatory efficacy and tolerability of dexamethasone intraocular suspension 9% and mirror those of the controlled Phase 3 clinical trials.

 Viewing these real-world results alongside those from the Phase 3 registration trials can be illustrative, especially regarding the patient population included.

FDA studies generally follow a fairly restrictive set of inclusion and exclusion criteria, whereas this real-world retrospective study included all patients at participating centres who had received dexamethasone intraocular suspension 9% during the allotted time period, providing a window into the drug’s performance in an ’unfiltered’ population, including patients with complicated ocular histories and comorbidities. Although there are some limitations to this type of real-world retrospective analysis, the insight gained can be very powerful.

Data from the aforementioned studies, as well as my own anecdotal observations, form the basis of my dexamethasone intraocular suspension 9% patient selection standards today. In my practice, 95% of cataract and combined cataract and minimally invasive glaucoma surgery (MIGS) procedures conclude with administration of this agent.

Although the pivotal trials for the drug were conducted in cataract surgery, it is approved for any ocular surgery, and is now routinely used for postoperative inflammation control in MIGS and even vitreoretinal surgeries.

 Some may wonder whether the option is suitable for every patient. It certainly has its merits; and it has been proven to be safe.

I consider nearly every patient to be a candidate for dexamethasone intraocular suspension 9%, based on its efficacy and safety profile. I find its ability to quell postoperative inflammation comparable to that of difluprednate ophthalmic emulsion 0.05% topical corticosteroid drops (Durezol, Novartis), which I previously relied on for most of my patients with cataract and cataract/MIGS.

Patients who may not be appropriate candidates for dexamethasone intraocular suspension 9% include those who are likely to need their corticosteroid dosage modified at a moment’s notice (e.g., known corticosteroid responders and patients who have advanced glaucoma). For known corticosteroid responders and those with advanced glaucoma, I would prefer to use a topical anti-inflammatory regimen that I could alter as needed.

In my experience with dexamethasone intraocular suspension 9%, IOP elevations in patients without additional risk factors may occur within the first few postoperative days; however, they resolve without intervention by the end of the first week. In general, the risk of severe or prolonged IOP elevation in patients treated with the agent is low; a post-hoc, pooled analysis of Phase 3 study data found that the risk of postoperative IOP elevation was comparable to that with topical corticosteroid therapy.

Dexamethasone intraocular suspension 9% has particular utility in patients with complex histories and/or inflammatory risk factors. Prior to the availability of this sustained-release formulation, I would occasionally administer a small amount of dexamethasone intracamerally to provide a boost of anti-inflammatory prevention in patients at risk of elevated postoperative inflammation, such as those with uveitis. Now I notice that when I administer dexamethasone intraocular suspension 9% to a patient with a history of uveitis, I see excellent inflammation control without the use of adjunctive topical corticosteroid.

As another example, I recently operated on a patient with diabetes who had an intraoperative iris bleed. I was able to wash out about 95% of the blood cells from the anterior chamber but could not clear the remainder. I injected dexamethasone intraocular suspension 9% into the posterior chamber and saw the patient at 1, 3 and 7 days postoperatively.

By Day 3, he had almost no cells in the anterior chamber, and by 1 week he was fully clear. This is the type of patient in whom I would normally expect to see significant inflammation and possibly even the need for additional postoperative corticosteroid eye drops, but neither of those issues occurred, which speaks to the potency of this drug.

In addition to using dexamethasone intraocular suspension 9%, I continue to prescribe a once-daily topical NSAID: either bromfenac ophthalmic solution 0.07% (Prolensa, Bausch + Lomb) or nepafenac ophthalmic suspension 0.3% (Ilevro, Novartis). One drop is easy for the patient to remember, and I have always given an NSAID postoperatively for prophylaxis of cystoid macular oedema.

The use of dexamethasone intraocular suspension 9% takes the responsibility of controlling postoperative inflammation out of the patients’ hands, which is helpful both to them and to me. The patients gain the convenience that comes with not having to procure topical corticosteroids, administer them correctly, or remember to use them multiple times a day, according to the tapering schedule. I benefit because I can be sure that patients have anti-inflammatory coverage in place, which in turn improves surgical outcomes.

Dr Savetsky is a board-certified cornea/external disease, cataract and refractive surgeon specialising in laser refractive surgery, corneal transplants and advanced cataract surgery. He is in private practice in Los Angeles, California, United States. Dr Savetsky is a consultant for EyePoint Pharmaceuticals.

1. McColgin AZ, Heier JS. Control of intraocular inflammation associated with cataract surgery. Curr Opin Ophthalmol. 2000;11:3-6.

2. Mentes J, Erakgun T, Afrashi F, et al. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Int J Ophthalmol. 2003;217:408-412.

3. Donnenfeld E, Holland E. Dexamethasone intracameral drug-delivery suspension for inflammation associated with cataract surgery: a randomized, placebo-controlled, phase III trial. Ophthalmology. 2018;125:799-806.

4. Donnenfeld ED, Solomon KD, Matossian C. Safety of IBI-10090 for inflammation associated with cataract surgery: phase 3 multicenter study. J Catract Refract Surg. 2018;44:1236-1246.

5. Weinstock R. Dexamethasone intraocular suspension 9% after cataract surgery: data from a retrospective study. Presented at: American Academy of Ophthalmology Annual Meeting; November 13-15, 2020; virtual.

6. Kiernan DF. Dexamethasone intracameral drug-delivery suspension for inflammation associated with vitreoretinal surgery. BMJ Open Ophthalmology. 2020;5:e000491.

7. Matossian C, Hovanesian J, Bacharach J, Paggiarino D, Patel K. Impact of dexamethasone intraocular suspension 9% on intraocular pressure after routine cataract surgery: post hoc analysis. J Cataract Refract Surg. 2020;47:53.

Evidence from clinical trials and real-world situations demonstrates the effectiveness and convenience of intraocular drugs to control postoperative inflammation. 

Real-world outcomes validate intraocular drug delivery method

Although there are currently no options available to treat retinitis pigmentosa (RP), one novel approach has been evaluated in a Phase 2 clinical trial carried out in this patient population. The study determined the clinical effect of injecting human retinal progenitor cells to improve vision and visual fields by activating and preserving retinal cells.

According to Dr David S. Boyer, adjunct clinical professor of ophthalmology at the Keck School of Medicine of USC in Los Angeles, California, United States, the findings indicated that this treatment may be able to enhance vision and visual fields in specific patients with RP whose living cells can be rejuvenated.

Method and endpoints of the retinal progenitor cell injection trial

A heterogeneous group of patients with RP and 20/80 to 20/800 vision were included in the trial. Patients were not excluded based on their clinical picture or genetics. Following exclusion due to administration of the wrong dose, loss to follow-up or a pre-existing condition, 74 patients were included in the study and randomised 1:1:1 in the analysis.

The cells given by injection were regenerative and intended to enhance those that might still be living in the retina. Three study groups were tested: patients who received an injection of 3 million cells; patients who received an injection of 6 million cells; and a sham control group. The goals were to determine the ideal dose of cells and identify secondary endpoints, and to determine the clinical characteristics of the patients who might benefit most from one intravitreal dose in a Phase 3 trial.

The primary endpoint was the mean change in the best-corrected visual acuity (BCVA) from baseline to month 12. The secondary endpoints were low light mobility to facilitate navigation through a maze, kinetic visual fields that map the remaining vision, contrast sensitivity and the results of a visual functioning questionnaire (VFQ-48).

Injection of the 6-million-cell dose produced a moderate improvement in vision of approximately 4.4 letters over the sham treatment. The kinetic visual field also showed an improvement, as did contrast sensitivity and results of the VFQ-48; however, Dr Boyer reported that no improvements were seen in the low luminance test.

In previous studies, Dr Boyer explained, it had not been possible to measure patients with a visual field of less than 12 degrees reliably, because of their inability to maintain fixation without central vision. Moreover, patients with a three-line difference in vision between the treated eye and the fellow eye also had a decrease in vision that could not be improved.

When the investigators evaluated the patients in the Phase 2 trial according to these specific parameters, they saw approximately 15 letters of improvement and significant improvements in the kinetic visual fields, contrast sensitivity, VFQ-48 and navigation through the low luminance maze when the patients in the 6-million-cell group and those who received the sham treatment were compared.

At the time of this article, approximately 130 eyes had been treated and the safety profile was excellent. No serious adverse events occurred in the group treated with the higher dose. “The study found that the 6-million-cell dose was the most effective, all clinical trial endpoints were useful and supportive of the treatment effect, the treatment had an excellent safety profile, and certain patients from the broad set of [patients with RP] studied can be assessed more reliably,” Dr Boyer said.

However, the question remains as to which patients would benefit the most from this treatment. Heat maps were generated that showed the width and the band of the ellipsoidal zone; the results indicated that its thickness may be predictive of improvements in the endpoints (BCVA, visual fields, contrast sensitivity, low luminance level in the maze and VFQ-48 results) with the human progenitor cell treatment compared with sham treatment. Similarly, the mean foveal central thickness was also highly correlated with improvements in the endpoints in the 6-million-cell group.

“The optical coherence tomography findings indicated structural predictors—i.e., the ellipsoidal zone thickness and the mean foveal thickness—for [participants] who received the 6-million-cell dose who were most likely to improve with injection of human progenitor cells,” Dr Boyer concluded.

“There was no evidence of structural improvement at 12 months. The potential minimal thickness should be considered as part of the inclusion criteria for future studies,” Dr Boyer added. The Phase 3 trial will begin in the third quarter of 2022.

This article was adapted from Dr Boyer’s presentation at the Bascom Palmer Eye Institute’s Angiogenesis, Exudation, and Degeneration conference, held virtually in February. Dr Boyer is a consultant to jCyte, which ran and participated in the study under discussion.

Trial results indicate that retinal cell injections improve vision in certain retinitis pigmentosa patients.

Targeting human retinal progenitor cell injections for retinitis pigmentosa

Results from a laboratory study measuring oxygen kinetics during corneal cross-linking (CXL) indicate that supplementary oxygen has the potential to substantially increase the efficacy of the procedure, according to Dr Theo G. Seiler, Jr, senior physician in the Department of Ophthalmology at the University of Bern in Switzerland. The laboratory study, which was performed using de-epithelialised porcine eyes, measured local oxygen concentrations at varying corneal depths under atmospheric (21% O2) and hyperoxygenic (100% O2) conditions with different levels of ultraviolet (UV) irradiation.

The analyses showed that, compared with the atmospheric oxygen environment, supplementary oxygen increased the amount of oxygen available in the stroma during CXL. Dr Seiler noted that the benefit of the hyperoxygenic environment was particularly seen when using higher UV irradiances that are associated with increased oxygen consumption.

“The mechanism of action for CXL involves UV-induced activation of riboflavin, the photosensitiser, resulting in the generation of reactive oxygen species that induce formation of covalent bonds within the collagen fibrils and crosslink the proteoglycans between the fibrils,” he said. “Many previous studies have investigated the influence of varying the parameters for riboflavin imbibition and UV irradiation on CXL effectiveness.”

Dr Seiler said that the study was motivated by the limited research investigating the role of oxygen, which is the third crucial factor for achieving sufficient CXL. “Our findings show that providing supplementary oxygen is likely to be beneficial by increasing the aerobic reaction and allowing more efficient CXL in deeper corneal layers and at UV irradiance levels less than 3 mW/cm2,” he said.

Measurement of the oxygen concentration at different corneal depths was accomplished by inserting a fibre probe into channels created by a femtosecond laser at depths of 100 μm, 200 μm and 300 μm. Eyes were exposed to 0.1% riboflavin (Vibex Rapid, Avedro/Glaukos) for 10 minutes, and then the oxygen concentration was continually measured during irradiation at 3, 9, 18 and 30 mW/cm2. “In order not to alter the cornea during the measurements, the used fibre probe had a tip that was only around 50 μm in diameter,” Dr Seiler said.

Groups of eight eyes each were evaluated under each of the testing conditions while the oxygen concentration was continually measured. Under atmospheric oxygen and with irradiation at 3 mW/cm2, representing the conventional Dresden protocol, there was a surplus of oxygen available at all measured depths during the entire CXL procedure.

However, when the irradiance was increased to 9 mW/cm2, sufficient oxygen for CXL was available only at 100 μm and 200 μm. At UV irradiance above 9 mW/cm2, all oxygen was consumed within the anterior 100 μm, indicating that there was insufficient oxygen for achieving sufficient cross-linking in the profound cornea, Dr Seiler said.

When the testing was done in the hyperoxygenic environment, there was sufficient oxygen available for cross-linking at all measured depths when using the 3 mW/cm2 and 9 mW/cm2 irradiances. At higher UV irradiances, there was more oxygen available than under atmospheric conditions, although still not enough to provide sufficient oxygen through the entire corneal stroma. Additional analyses determining the consumption of oxygen showed that during the procedure, the half-lives were longer and the depletion rates higher with supplementary oxygen, suggesting a more efficient CXL than under atmospheric oxygen conditions, said Dr Seiler.

This article is based on a presentation given by Dr Seiler at the 2020 ESCRS Virtual Congress. The study was published (Seiler TG, Komninou MA, Nambiar MH, et al. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. 