Louise Gagnon

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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.”

The eye lane triangle method is demonstrated, including positions for the examiner and patient. (Image courtesy of Mr Jeff Locke)

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.

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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

Ophthalmologists have several options at their disposal for the treatment of presbyopia, according to Dr Elizabeth Yeu, a partner at Virginia Eye Consultants and an assistant professor at Eastern Virginia Medical School in Norfolk. Speaking recently at the virtual 2022 Toronto Cataract Course, Dr Yeu noted that innovation is advancing in presbyopia correction. “We have spent a very long time without much in the way of innovation beyond the realm of glasses and lenses,” Dr Yeu said. “It is a booming field. We know there are a lot of presbyopes worldwide, and the market [for presbyopia management] is huge. It is only growing exponentially.”

There are noninvasive options for presbyopia correction, such as glasses, multifocal contacts, and eye drops. Additionally, surgical options include LASIK, inlays, and refractive lens exchange, Dr Yeu explained. “There [are] a variety of different miotic drops being used, some individually and some in combination [with another treatment],” she said.

The key measurement of efficacy used by the US Food and Drug Administration (FDA) is an improvement in vision of 2 to 3 lines in a 6-hour window, Dr Yeu noted. Some drop options include FDA-approved Vuity, which has pilocarpine as the active ingredient and is a miotic. Brimochol is an investigational treatment that offers near vision improvement and is a combination of carbachol with brimonidine tartrate.

One of the considerations with topical formulations to correct presbyopia is bioavailability. “A better formulation means better bioavailability and a reduced concentration [of the active ingredient] so there are fewer [adverse] effects, [such as] blurred vision, headaches, and brow aches,” Dr Yeu said.

Moreover, another treatment option under investigation in eye drops includes CSF-1 by Orasis Pharmaceuticals, which uses a lower concentration of pilocarpine. PRX-100 is also a miotic therapy, which has aceclidine as an active ingredient. Another novel therapy under investigation is a combination of phentolamine mesylate and pilocarpine, known as Nyxol, which acts as a miotic and vasodilates small muscles, Dr Yeu explained.

One of the novel topical agents is lipoic acid choline ester, which is made to soften the lens and can work in conjunction with a miotic agent to promote accommodation. Another combination to correct presbyopia is True Vision Treatment contact lenses and eye drop kit by Yolia Health, which is a treatment designed to alter the cornea.

Collagen cross-linking may also potentially represent an option in presbyopia correction. “Instead of using it centrally for myopia or keratoconus, if we were to use it in the midperiphery, creating an effective steepening of the centre, this could be used for [patients with presbyopia],” Dr Yeu said, noting that anterior optical coherence tomography images display the central steepening that collagen cross-linking can create.

Synthetic inlays may not be very well tolerated by the human cornea, but allogenic inlays, which are extremely thin, may hold promise, according to Dr Yeu. “If we can get rid of the antigenicity of it, the scaling potential is huge,” she said. “There can be a 3-line improvement in a patient’s near vision improvement.”

One of the factors to consider is ocular rigidity and its impact on presbyopia. “Ocular rigidity is a source of presbyopia in multiple ways,” she said. “It causes scleral rigidity and makes it worse in terms of what happens in the zonules. There is increased lens stiffening.”

A procedure known as laser scleral microporation targets scleral rigidity by “uncross-linking,” potentially helping with biomechanical softening, improving ciliary muscle efficacy to relax the zonules, reshaping the lens during accommodation, and minimizing positive spherical aberration, Dr Yeu explained. She also noted that 10-year data on patients suggest that 3-line improvement in near vision is maintained.

Ophthalmologists have a variety of lenses available for presbyopia correction, including trifocal IOLs, bifocal IOLs, monofocal IOLs, enhanced monofocal IOLs, enhanced trifocal IOLs, and extended depth of focus (EDOF) IOLs. “The enhanced monofocal [IOL] can be used in any patient [in which] you would use a monofocal lens,” Dr Yeu said. However, Dr Yeu also noted that enhanced monofocals are not classified as EDOF lenses and that presbyopia correction options are being tailored to specific corneal issues, such as post radial keratotomy, post LASIK, keratoconus, and iris trauma.

In selecting IOLs for patients, clinicians must consider a patient’s lifestyle, hobbies, and activities. It is also important to evaluate a patient’s tolerance of visual disturbances, such as halos and rings around lights at night, Dr Yeu explained.

Other exciting options on the horizon for presbyopia correction include modular accommodating lenses, Dr Yeu noted, adding that vision gains in studies are impressive. “[Lenses] are very close to entering phase 3 studies,” Dr Yeu said. “[Lenses] are fluid filled and would provide accommodation. The base is first inserted, followed by the insertion of the optic. Because it is completely filling the bag, no [posterior capsule opacification] has been seen in any of these patients, which is very important.”

The hurdle in integrating this IOL into clinical practice may have to do with concerns about insertion of the base of the IOL. However, Dr Yeu said that advances in presbyopia correction and what is in pipeline are certainly encouraging. “It is exciting to see where we were 5 to 7 years ago vs where we will be 10 years from now, with respect to various options and what we will offer in presbyopia correction,” she said.

Yeu is a consultant for and does research with Tarsus Pharmaceuticals and Alcon.

Thanks to recent innovation, ophthalmologists have several options at their disposal for the treatment of presbyopia.

Medical and surgical treatments emerge for presbyopia

A novel treatment for dry eye disease (DED) in the form of topical oestradiol can reduce signs and symptoms of DED in postmenopausal women for at least 3 months, according to Dr Gerhard Garhöfer, associate professor at Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria. Dr Garhöfer served as lead investigator for a randomised, controlled, parallel-group study of the therapeutic formulation of oestradiol candidate RP101 (Redwood Pharma).

“Sex hormone receptors or oestrogen receptors have been found to be present on the ocular surface in several tissues, such as the conjunctiva, cornea and Meibomian glands,” Dr Garhöfer said. “The pronounced contrast in dry eye prevalence between men and women, especially women who are postmenopausal, points towards an involvement of sex hormones in the disease process. Furthermore, anti-oestrogen treatment seems to disrupt tear production.”

RP101 contains 17-beta-estradiol as the active ingredient and a sterile isotonic thermogelling (IntelliGel) solution as the drug delivery system. This thermosensitive, supramolecular hydrogel becomes a gel at eye temperature, allowing for a long period of residency on the ocular surface and thus permitting sustained drug delivery.

Dr Garhöfer and his co-investigators enrolled 104 patients in the study, with 77 completing the study according to the protocol. Five patients requested withdrawal, 21 withdrew due to adverse events and one withdrew for other reasons.

The study aimed to determine the optimal dosing regimen of RP101 and to evaluate its safety in postmenopausal women with moderate-to-severe DED. The four arms of the study included 0.05% twice daily, 0.1% morning and vehicle (isotonic thermogelling solution) in the evening, 0.1% twice daily and a control group who received the vehicle twice daily. The treatment period was 3 months.

Investigators used Schirmer’s test II and grading of corneal fluorescein staining, taking measurements at baseline and at various points during treatment: Day 14, Day 30, Day 60 and Day 90 (treatment completion). Patients reported outcomes for various DED symptoms via the Symptom Assessment Questionnaire iN Dry Eye (SANDE) and the Visual Analogue Scales (VAS).

Corneal fluorescein staining score significantly decreased during the 3-month treatment period(

< 0.001 vs baseline). Investigators found no significant difference between treatment groups. The staining of the inferior cornea, however, showed a significantly more pronounced reduction in the highest-dose group compared with vehicle (

Schirmer’s test II showed an increase in tear production, reaching maximum effect after 90 days of treatment. “Schirmer’s Test II increased significantly after 14 days of treatment in the active groups and after 1 month of treatment in the control group and remained significantly elevated until the end of the study,” Dr Garhöfer explained.

The SANDE symptom score, a frequently used standardised questionnaire for assessing the severity and frequency of dry eye symptoms, showed a decrease at the end of the treatment period in all groups. Moreover, patient-reported outcome via VAS in all four treatment arms showed a decrease in symptoms of DED, such as foreign body sensation; burning/stinging; itching; pain; sticky feeling; redness; and tearing.

The eye drops were well tolerated on the ocular surface and showed a favourable safety profile. “Most treatment-related adverse events were eye-related and mostly mild or moderate,” Dr Garhöfer said. “The most frequent … (more than 5% in at least one treatment group) were blurred vision; eye pain; eye irritation; ocular hyperaemia; eyelid swelling; or foreign body sensation. All these adverse events had resolved at the end of the study.”

According to Dr Garhöfer, at this time therapy data are limited to use in postmenopausal women. “Further studies are needed to investigate whether other target populations would benefit from topical oestrogen treatment.” He added that the next step will be a Phase 3 study, which will be designed based on the data obtained from the Phase 2 study. 

“Our data show that all dosages of RP101 were safe and improved signs and symptoms of DED at the end of the observation period,” he said. “We think the topical approach would make the most sense in dry eye patients as it can reach higher levels on the ocular surface while not needing high plasma levels, which would be the case when oestrogen is given systemically.”

Dr Garhöfer did point out, however, that the thermosensitive hydrogel solution that served as a control in the study also had an impact on signs and symptoms of DED. He said that systemic oestrogen is not a preferred option to treat DED in postmenopausal women because it has been linked to serious systemic adverse effects. He concluded, though, that “with a topical formulation, systemic uptake of oestradiol is very low, which limits the risk of systemic side effects.”

This article is based on Dr Garhöfer’s presentation at the 2021 annual meeting of the Association for Research in Vision and Ophthalmology. Dr Garhöfer has no financial disclosures to declare related to this content.

Investigators find that oestradiol drops can ease signs and symptoms for 3 months.

Austrian study targets dry eye disease in postmenopausal women

Additional data on novel autoantibodies related to Sjögren’s syndrome (SS) may improve screening of dry eye patients for SS, according to research presented at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. The study, funded by the National Eye Institute, was led by Dr Vatinee Bunya and presented by Kennedy Johnson, a clinical research coordinator at the Scheie Eye Institute at the University of Pennsylvania in Philadelphia, United States.

SS is an underdiagnosed autoimmune disease in which the diagnosis is often delayed by a few years. “Because dry eye is one of the most common symptoms of the disease [SS], ophthalmologists often see these patients first and are therefore in a unique position to screen dry eye patients for SS,” Ms Johnson said. However, because this symptom is so prevalent, it is not feasible to screen all patients with dry eye for SS, she noted.

There are traditional antibodies used to check for SS. These include anti-SS-related antigens A and B (SSA, SSB), antinuclear antibody (ANA) and rheumatoid factor (RF)-related antigens A and B; however, Ms Johnson noted that these antibodies are not specific to SS and are not found in every patient with SS. Previous research

 to evaluate dry eye patients for SS found that half required a minor salivary gland biopsy to reach a definitive diagnosis because of the lack of positive antibody testing, Ms Johnson explained.

“We believe it is important to identify new serological biomarkers that could better characterise SS and overcome the limitations of traditional antibodies,” she added. “Many studies have explored novel antibodies for SS.”

One of those studies concluded that antibodies to salivary protein, parotid secretory protein and carbonic anhydrase isoenzyme VI (CA-VI) may be novel markers for SS, said Ms Johnson. Moreover, in mouse studies these novel antibodies were detected earlier in the disease process.

Other research has revealed that anti-CA-VI is associated with younger age and more severe disease,

 noted Ms Johnson. Studies have found that autoantibodies SP-1 IgM and PSP had increased prevalence in patients with SS and that SP-1 may be a marker of worse ocular surface disease.

 She pointed to research which suggests that autoantibodies may not only help detect patients with SS but also detect those with more severe disease.

Dr Bunya and her team at Scheie Eye Institute had previously developed a screening questionnaire including ocular examination findings such as tear film break-up time and lissamine green staining of the conjunctiva, to help detect patients with dry eye who may also have underlying SS. The sensitivity of the algorithm was 78% and the specificity 66%.

Since then, the team has sought to refine the diagnostic ability of the tool and increase the sensitivity and specificity by incorporating novel autoantibody data. They launched a study including patients with dry eye who were older than 18 years and had no previous diagnosis of SS or any other autoimmune disease.

They excluded patients with a history of corneal refractive surgeries, head or neck radiotherapy, chemotherapy or pre-existing lymphoma, and patients taking a topical glaucoma medication. Ms Johnson stated that as a definition of SS, they used classification criteria as developed by the American College of Rheumatology and the European League Against Rheumatism.

In addition to completing the questionnaire, subjects in the study also underwent an ocular surface examination, an unstimulated salivary flow rate test and serological testing. A subset of subjects also underwent a labial salivary gland biopsy if indicated.

Investigators found that the percentage of positive subjects in the specific immunoglobulin groups of SP IgA, PSP IgM and CA-VI IgM was significantly higher in those with SS than in those without SS. “We had 25.4% in the absence of SS and 61.1% in the presence of SS,” said Ms Johnson.

She noted that including the autoantibodies SP IgA, PSP IgM and CA-VI IgM produced an improvement in the performance of the previously developed algorithm. However, she stated that the study must be conducted in a larger, more diverse population to ensure that the screening method can effectively be generalised.

“Our study has some limitations,” she said. “Our sample size was small and only involved a single centre, with the majority of patients being older Caucasian females.”

She added that in the future, investigators would like to include additional sites and a more diverse patient population to increase the generalisability of the screening tool. “Future studies may also involve the analysis of tear and saliva samples, which were collected during our study to further examine the presence of these autoantibodies and other biomarkers in patients with or without SS,” she said.

Dr Bunya is co-director of the Penn Dry Eye and Ocular Surface Center and associate professor of ophthalmology at the Hospital of the University of Pennsylvania, US. She did not indicate any proprietary interest in the subject matter.

1. Akpek EK, Klimava A, Thorne JE, Martin D, Lekhanont K, Ostrovsky A. 

. Evaluation of patients with dry eye for presence of underlying Sjögren’s syndrome. 2009;28:493–497.

2. Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjogren’s syndrome. 

3. Karakus S, Baer AN, Agrawal D, Gurakar M, Massof RW, Akpek EK. Utility of novel autoantibodies in the diagnosis of Sjogren’s syndrome among patients with dry eye. 

4. Bunya VY, Ying G, Maguire MG, et al. Prevalence of novel candidate Sjogren’s syndrome autoantibodies in the dry eye assessment and management (DREAM) study. 

5. Bunya VY, Masaro-Giordano M, Vivino FB, et al. Prevalence of novel candidate Sjogren syndrome autoantibodies in the Penn Sjogren’s International Collaborative Clinical Alliance Cohort. 

6. Bunya VY, Maguire MG, Akpek EK, et al. A new screening questionnaire to identify patients with dry eye with a high likelihood of having Sjogren syndrome. 

New serological biomarkers could characterise Sjögren’s syndrome better than traditionally used autoantibodies.

Author | Louise Gagnon

Articles

Medical and surgical treatments emerge for presbyopia

Austrian study targets dry eye disease in postmenopausal women

Challenges with screening dry eye patients for Sjögren’s syndrome

Finding ways to finesse eye examinations in paediatric patients