The need for, and benefits of, neonatal screening for ocular disease and vision screening during childhood is supported by the World Health Organization (WHO).1 Peak professional bodies, such as the American Academy of Pediatrics (AAP) and the United States Preventive Services Task Force (USPSTF), routinely examine the available and emerging evidence to support the recommendation of vision-screening programs and develop guidelines for their implementation. These guidelines are summarily endorsed or adopted by relevant professional organisations worldwide, as well as by the Royal Australian College of General Practitioners,2 Australian National Health Policy Frameworks,3 and Australian Government commissioned reviews of the literature and health policy.4,5

As we continue to rely on evidence-based medicine to guide health policy, in the absence of strong evidence, professional consensus is reached to determine utility. The optimal time (or times) for screening, the tools and techniques used, the personnel required, as well as the sensitivity of the screening methods used to detect disease, are not yet adequately defined. However emerging evidence continues to be evaluated to determine policy recommendations.

NEONATAL SCREENING

The WHO mandates universal screening of the newborn infant for any signs of ocular malformation or disease by macroscopic inspection and performing the red (fundal) reflex test for any anterior segment or intraocular disease. This should occur within the first six weeks of life.6 While the identification of disease present at birth is critical, not all eye disease will be obvious or even be present at this time. Many conditions can be developmental, thus a normal examination at birth does not confer normal ocular development for life.

Red (fundal) reflex screening is critical to identify significant and potentially blinding eye disease, such as cataract and even retinoblastoma. The significance of leukocoria in any child is sufficiently high that referral to an experienced specialist is always warranted.

The technique for red (fundal) reflex screening can be challenging for the novice practitioner. Ensuring the room is dimmed, and the examiner’s ophthalmoscope is positioned at least more than one metre away will greatly assist in the physiologic dilatation of the child’s pupils, which is required for the most reliable result. Moreover, when the examiner is unaccustomed to the ethnic variations that can be seen in children with darker pigmentation, false positive results can regularly arise. As with any technique, with practice comes proficiency, and the ability to examine the most difficult or non-compliant child.

That said, red (fundal) reflex screening is far more reliable at detecting anterior segment than posterior segment disease.

VISION SCREENING

There is no argument that vision screening in childhood can and does reduce the prevalence of preventable vision loss in childhood. In 1999, the WHO launched the Vision 2020 global initiative to eliminate preventable vision impairment, prioritising the control of childhood blindness.1 In this landmark report, it was estimated that a total 1.4 million children were blind worldwide, that 73% of them lived in lower middle-income countries, and that 40% of childhood blindness was avoidable. It was argued that without strategies to improve earlier diagnosis and treatment of preventable or treatable paediatric eye disease, and ensure access to treatment, this number would continue to increase to an estimated two million children by the year 2020.1 The WHO identified
the most common causes of childhood blindness as congenital cataract, retinopathy of prematurity, uncorrected refractive error, and corneal scarring from infectious disease (i.e. rubella or trachoma) or nutritional deficiencies (i.e. vitamin A deficiency).

The scope of meeting the WHO challenge is largely limited to screening and providing timely treatment for common, paediatric eye disease. Strabismus is not specifically included as a target disease, although as an amblyogenic risk factor, it would be detected during vision screening. In its most recent report, the WHO continues to promote screening at various timepoints throughout life, including in the neonatal period, and vision screening at three to five years of age.7

Within Australia, each state or territory has established its own vision screening programs for children at three to five years of age.

Not surprisingly, there is variation between the programs, not all children present for screening opportunities, and not all programs are regularly evaluated. To this end, the Vision 2020 Prevention and Early Intervention Committee assembled a multi-professional group of eye health care professionals including orthoptists, ophthalmologists, and optometrists to establish and reach a consensus agreement on a framework for a national minimum standard for vision screening in three to five-year-old children. The report can be accessed at Vision 2020 Australia’s website,8 and more information about the collaboration between the eye health professionals is reported by others, elsewhere in this issue. However, the basic premise of the minimum standards framework agreed that:

• Within Australia, all children between the ages of 3.5–5 years should have equal access to vision screening.

• Minimum standards for examination (including vision chart and optotypes) and referral criteria be accepted and should be adopted nationally.

• All caregivers should be provided with information to improve engagement with vision screening opportunities for their child.

• Post-screening pathways must be established to ensure any child identified as requiring further follow-up receives the assessment and care required.

• Evaluation programs must be embedded in any vision screening program.

• Eye screening should be modelled on the highly successful and formally evaluated Statewide Eyesight Preschooler Program (StEPS) in New South Wales.9

As the child progresses in their development, there is an increased focus on the development of myopia. Vision screening in the 5–18-year age group is also recommended by the WHO,7 particularly to identify vision impairment that may interfere with learning and education, as well as the early identification of myopia. Early diagnosis of myopia not only facilitates the opportunity for the provision of corrective lenses to improve vision, but also allows for the implementation of strategies that could reduce myopia progression, thereby mitigating the morbidity associated with moderate to high degrees of myopia.

Finally, it is not sufficient to have an efficient screening program. Once a child is identified as having a vision problem requiring attention, they should have fair and equitable access to timely and affordable confirmatory examination and treatment. Ensuring appropriate referral pathways are established, from the screener to eye care providers with the expertise to examine and treat the condition identified, is what makes screening effective. Referring the right child at the right time to the right person supports the most judicious use of the limited paediatric eye care workforce that currently exists. If less complex eye disease is managed in the community by suitably trained optometrists and orthoptists, the more complex eye disease can be managed at specialist centres by orthoptists and ophthalmologists. This collaborative approach would greatly relieve the burden on specialist centres, as well as de-centralise paediatric care where possible. This is particularly relevant for children in regional and rural areas.

TARGETED SCREENING FOR FAMILIAL EYE DISEASE AND AT-RISK CHILDREN

Screening for common paediatric eye disease, such as refractive error and amblyopia,
is efficient because the prevalence is high enough to warrant it, these eye conditions are easily treatable, and by and large there is ready access to treatment. Some paediatric eye diseases, however, are not common and thus screening on a large scale for such diseases is not recommended – except in the case of familial eye disease. Common heritable eye diseases, such as strabismus and refractive error, as well as less common eye diseases, such as cataract, retinoblastoma, and congenital or infantile glaucoma, certainly benefit from the earliest possible diagnosis.

Strabismus and Refractive Error

It is known that strabismus and refractive error can be a familial trait. Thus, when a family history of strabismus of any type, or refractive error is present, there could be a heightened expectation that the offspring may develop the same condition. When a parent provides consent for their child to undergo vision screening, the family history is recorded, as this may increase suspicion regarding the likelihood that the child may be similarly affected. Currently, there are no specific guidelines to recommend frequent screening of children with a family history of strabismus and refractive error. However, early diagnosis and treatment of strabismus and refractive error can reduce the development of amblyopia. Caregiver education may promote awareness to recognise signs of strabismus or poor vision and prompt seeking health advice sooner.

Cataract

As outlined earlier, nationwide screening of every newborn with the red (fundal) reflex test should, in theory, detect every child born with cataract. This is not the case, and many children will present after the newborn period as the cataract may develop later. Knowing there is a family history of cataract can prompt closer and more frequent review of an infant, as their cataract may not be present or noticeable at birth. If the family is falsely reassured of the absence of cataract at birth, they may not realise that cataract is developing until it significantly impacts the child’s vision development. The presenting sign may now be leukocoria, strabismus, or – in the presence of dense, bilateral visual deprivation – sensory nystagmus. Any family history of childhood cataract should be carefully considered, and the infant referred for ongoing surveillance. This will enable the earliest diagnosis of cataract development, and prompt treatment to achieve the best visual outcome.

Not all cataracts in infancy will be dense and nuclear; there are a variety of phenotypes, many of which may be heritable. Where there is a known family history of cataract in childhood, it may be possible that the causative familial gene is known, and the child can be tested. This would obviate the need for repeated examinations or ongoing parental anxiety about the development of this potentially blinding eye disease.

Glaucoma

As with cataract, not all children with glaucoma will have obvious signs of disease at birth. Characterised by any one or more of the following: raised intraocular pressure, buphthalmos, epiphora, photosensitivity or corneal opacification (which can often look ‘steamy’), glaucoma may not be readily obvious until the irreversible damage is done. Any child with a family history of congenital or infantile glaucoma should be referred to an ophthalmologist for ongoing surveillance so that the earliest signs of glaucoma can be recognised, and treatment commenced to avoid permanent vision impairment. Also, as with cataract, the glaucoma phenotype may not be the same as the parent, so careful examination and consideration must be given to the frequency and intervals for review. Similarly, if the familial mutation is known, genetic testing may guide the need for ongoing screening.

Retinoblastoma

Retinoblastoma is the most common intraocular malignancy to occur in children under the age of five years.10 Although it is rare, it accounts for almost 10% of all cancer in children under the age of one year.11 In a high-income country, the most common presenting signs are leukocoria, strabismus and increasingly, family history of disease. In countries like Australia and New Zealand, with early diagnosis and access to treatment, survival is almost 100%.12 With such a high survival rate come survivors who may carry a heritable germline mutation that can be passed on to their offspring. Since transmission of RB1 mutations occurs in an autosomal dominant inheritance pattern, each pregnancy is at a 50% risk of being affected.13 All survivors with bilateral disease, and approximately 15% or more of those with unilateral disease will harbour a germline, therefore heritable, mutation.14 Older age at presentation and laterality does not confer a diagnosis of non-heritable disease, as this can only be conclusively established by genetic testing. All offspring of retinoblastoma survivors require some form of screening until informed by genetic testing. The infant can be discharged from screening when it can be conclusively proven that either the parent has non-heritable retinoblastoma, or the child has not inherited the familial RB1 mutation.

Failure to adequately screen children with a family history of retinoblastoma has resulted in infants presenting symptomatically with extensive disease and limited treatment options. Conversely, early screening of children with a family history of retinoblastoma ensures survival and is associated with higher rates of globe salvage.15 Depending on tumour size and location, vision can be preserved.

Although the early detection of retinoblastoma is listed as one of the reasons for conducting the neonatal red (fundal) reflex in all infants, it is not as effective as screening for cataract since tumours at this age are likely too small to elicit an abnormal fundal reflex.16 In the past 30 years, no child in Victoria or Tasmania with a retinoblastoma diagnosis was identified via the neonatal red (fundal) reflex screening referral pathway; several were missed (unpublished data, South-East Australian Retinoblastoma Database). What is efficient though, is screening at-risk offspring, that is, children of adult retinoblastoma survivors. As a rare disease, we must acknowledge the limitations of population-based screening to detect retinoblastoma as neither efficient nor practicable, however targeted screening in this population is very effective.

Ideally, all adult retinoblastoma survivors planning a family should be referred to their nearest retinoblastoma treatment team. This will provide the opportunity to confirm their genetic status or arrange further genetic testing and counselling with technology that was not available at the time of their diagnosis. This can inform their family planning choices or assist in planning the screening of their baby during pregnancy and following delivery. Infants of adult retinoblastoma survivors should be referred urgently to a retinoblastoma treatment centre for examination by ophthalmologists who are expert in the diagnosis and management of this condition. If genetic testing has not been undertaken or fully informative, this will be arranged, and appropriate screening continued until a result informs ongoing requirements for examination.

GENETIC TESTING

When considering heritable eye disease, genetic testing has been a game-changer. There is a growing laundry list of gene variants associated with the development of cataract (e.g.EPHA2, GJA3, GJA8)17,18 and fewer for glaucoma (e.g. MYOC, CYP1B1).19 For retinoblastoma there are currently only two – RB1(heritable or non-heritable)20 and amplification of the MYCN gene
(non-heritable).21,22 With the advent of genetic testing though, establishing whether the child has indeed inherited the familial mutation can inform the need for, or the intensity of, screening for the familial disease.

Particularly for retinoblastoma, genetic testing has changed the treatment landscape for children thought to be at risk. Where the heritable, germline mutation is known, genetic testing can support family planning choices including the use of pre-implantation genetic testing and in vitro fertilisation technology to achieve an unaffected pregnancy. Alternately, for naturally conceived pregnancies, the foetus can be tested pre- or immediately postnatally to determine whether the familial RB1 mutation has been inherited. This has a significant impact on the infant. Without genetic testing, they could endure up to 13 examinations under general anaesthesia within their first five years of life to enable a dilated, indented fundus examination to visualise tumours
at their smallest, when they may be treated with focal therapy alone. Thus, in the setting of retinoblastoma, genetic testing does significantly impact on the intensity and invasiveness of the screening they receive.

CONCLUSION

We know screening for paediatric eye disease is not only important; it is essential. Identifying eye disease while the visual system is developing is critical to achieving the best outcomes for the child.

When we think of screening, we need to think beyond the traditional sense of vision testing at pre-school age to also consider targeted screening that we, as eye health professionals, can be alert to.

The adult with a history of congenital cataract, glaucoma, retinoblastoma or even strabismus and amblyopia, should always be provided education around their eye disease and the possibility of its heritable nature. They may be unaware of the significance, simply because they were too young when they were treated, and the discussion around heritability was had with their parents and not them.

With any paediatric eye disease, “an early diagnosis is the best cure”.23

References available at mieducation.com.