Leukocoria and Strabismus A Red Flag Until Proven Otherwise

However, for many eye conditions, the early signs may appear innocuous or can even be masked because the child will not complain or necessarily behave as if they have a visual problem.

Caregivers are the greatest advocates for their child’s health. What they notice can be critical; we clinicians must respond appropriately.

Case in point: A mother presents to her general practitioner (GP) with her 4.5-monthold baby and then to her paediatrician having noticed intermittent left esotropia over the previous few weeks (Figure 1A). The baby was seven weeks premature, but there was no family history of any ocular disease, and the baby was otherwise well and thriving.

The parents were advised by their doctors that the baby was still young, and abnormal ocular alignment at this age was not uncommon,1,2 particularly with the baby’s history of prematurity.3,4 The ocular fundus was not examined, and no referral was made for review. The parents were advised to watch and wait, and left reassured.

One week later, the parents noticed leukocoria in the baby’s left eye in some, but not all, of the many photographs they were taking (Figure 1B). They dismissed this observation until, quite coincidentally, they saw a television news story describing a child being diagnosed with retinoblastoma after the parents had noticed intermittent leukocoria across the table at dinner time. The baby’s parents recalled the images they had taken and returned to their GP. Now very concerned, they requested a referral to an ophthalmologist regarding the leukocoria.

Seen promptly, their worst fears were confirmed – their little baby had retinoblastoma (Figure 2, above). Although the tumour was small, it encompassed the macula sufficiently to disrupt her binocular function and cause her strabismus, eliciting the leukocoria in photos.

This is not an uncommon story, anywhere in the world.

Data from Victoria showed 63% of parents visited two or more primary healthcare providers and 40% required three or more visits before a referral to an ophthalmologist was obtained and a diagnosis of retinoblastoma was made; only just over a third (37%) were referred at their first consultation with a primary healthcare provider.5

Leukocoria and strabismus are not benign entities until proven otherwise.

A PLETHORA OF DIFFERENTIALS

Myriad diagnostic differentials should be considered with a presentation of leukocoria or strabismus. The most common causes of leukocoria include cataract, retinoblastoma, Coats disease, retinal detachment, persistent foetal vasculature, coloboma, infection (toxoplasmosis) or inflammation.6 Most strabismus will be of primary origin,7 with associated risk factors including refractive error, prematurity, low birth weight, and maternal smoking.3,4 Secondary strabismus can be a sign of more sinister pathology including: systemic disease8 and intracranial9 or intraocular pathology.10 Of course, sensory strabismus may also occur in the setting of severe vision loss or amblyopia.11

Unless the pathologic cause of leukocoria and strabismus is advanced, these conditions are essentially painless. Hence, the absence of pain as a symptom should not delay helpseeking or referral for further investigation.

THE GREAT PRETENDERS

Both leukocoria and strabismus are also ‘great pretenders’ as they can occur due to photographic artefact or be related to normal growth and development. This can lead to complacency or dismissal of a sign that is, in fact, critically important.

Leukocoria

• The angle of the photograph where light bounces off the optic nerve head.12
• 2) Since the advent of smartphone cameras, photo-leukocoria is a common observation and a readily dismissed observed sign.

Strabismus

1) Pseudostrabismus,13

2) Transient neonatal strabismus,1,2 and

3) Strabismus in high-risk groups: family history, prematurity, associated syndromes.3,4

However, both benign and pathologic causes of either leukocoria or strabismus, in the absence of other symptoms, can appear absolutely identical, thus requiring careful assessment to exclude significant pathology.

ESSENTIALS OF ASSESSMENT

Any parent presenting with their child – irrespective of their age – who reports having observed leukocoria or strabismus must be taken seriously. Moreover, take care to actively listen to the parents’ description of their observations. Many different words will be used to describe either leukocoria (glow, hologram, bubble, flash, shimmering)14 or strabismus (cross-eye, lazy eye, wall-eyed, not focussing or tracking).

Whatever the case, all differentials – irrespective of how rare or unlikely – must be considered and systematically excluded.

Parents will likely have photos on their smartphone to demonstrate what they have observed – take the time to look at them carefully. They will also have very likely consulted ‘Dr Google’ and be concerned. You can only allay their concerns if you have completed an examination.

Assessing Leukocoria

1) Inspect the eyes carefully in natural light – is there any evidence of leukocoria with the naked eye?

2) Examine the red (fundal) reflex. With the child seated comfortably on the parent’s lap, dim the room lights to slightly dilate the pupil without using mydriatic eye drops and examine the red reflex with an ophthalmoscope. One such exam is demonstrated at: youtube.com/watch?v= UO_pez7H8js. Be careful to perform this assessment from different angles, not just the primary position, as the pathology causing the leukocoria, e.g., retinoblastoma, may not be at the posterior pole, but rather the peripheral retina.15

3) Compare the reflex obtained between the two eyes, and be mindful that ethnic differences will give rise to a darker reflex in children of Asian or African descent compared to the reddish-orange reflex seen in Northern Europeans.16

Assessing Strabismus

1) The easiest, least-invasive method for assessing the presence of strabismus at near fixation is to examine the corneal light reflex. Hold a light source at approximately one third of a metre from the child – with a noisy toy for interest and attention – to assess the symmetry of the corneal light reflex.

2) Introduce cover with your hand (palm or occluder) of either eye at near and distance fixation to assess ocular alignment.

3) Whether you identify the presence of strabismus or not, additional assessment or history is also required to assist with determining the urgency of the referral that is required.

1. ALWAYS examine the red (fundal) reflex. Strabismus in every child should be considered secondary to pathology until proven otherwise. Strabismus is the second most common presentation for cataract17 and retinoblastoma.18
2. ALWAYS assess for associated neurologic or systemic symptoms that raise suspicion the strabismus is not benign.19
3. ALWAYS attempt to view the optic nerve to evaluate the presence of any disc swelling.

4) Remember the direction of deviation or frequency of strabismus are not determined by the pathology. Intermittent strabismus is not uncommon with intraocular pathology.

5) Examine the child’s ocular movements, looking carefully for any sign of neurogenic palsy that could account for the deviation.

REFERRAL PATHWAY

If your assessment confirms the presence of leukocoria or strabismus, what you do next is crucial. Evidence-based referral guidelines developed by the Department of Ophthalmology at the Royal Children’s Hospital, Victoria can be accessed at: rch.org. au/ophthal/for_health_professionals.

These guidelines largely apply across Australia and New Zealand.

Leukocoria

In brief, ANY concern about leukocoria – seen with the naked eye or red reflex – should be referred promptly. In the first instance, the child requires clinical review by an ophthalmologist or ophthalmology team. Per the recommended guidelines, contact the on-call ophthalmology registrar by telephone at the nearest paediatric hospital or ophthalmology clinic (particularly in rural/regional areas). They will advise on how to have the child assessed within the next day or days. If you have any photographs to support your findings, these will be helpful.

If there is no associated history of head/ ocular injury or systemic illness, the child does not need to be sent via an emergency department (ED) as this only serves to overburden already busy EDs.

Strabismus

In the case of strabismus, your additional assessment will determine the urgency of your referral. If the red reflex test or optic nerve assessment are concerning, or if the child has associated neurologic or systemic signs, the referral pathway as for leukocoria is appropriate.

If the red reflex is normal, and there are no other concerns, referral to a local optometrist, ophthalmologist or eye outpatient clinic is appropriate. Children under seven years of age with strabismus ideally would be investigated by an eye healthcare provider within two weeks of presentation. An optometrist or orthoptist with the necessary skills and expertise in ophthalmic examination may be best placed to achieve assessment within this time frame. Escalation of the referral to ED or an ophthalmologist or orthoptist can be arranged if the initial assessment findings require it.

CONCLUSION

Leukocoria and strabismus may be of no concern, or they may be a red flag for something serious.

Your assessment and prompt referral can significantly impact the child’s outcome.

Dr Sandra E. Staffieri AO is a Research Fellow at the Centre for Eye Research Australia (CERA) and the Retinoblastoma Care Co-ordinator/Senior Clinical Orthoptist at the Royal Children’s Hospital, Victoria.

Dr Staffieri completed her PhD at CERA, University of Melbourne. With the aim of reducing delayed diagnosis of retinoblastoma, her study included the development and evaluation of an information pamphlet for new parents describing important early signs of eye problems in children.

References

1. Horwood, A.M., Maternal observations of ocular alignment in infants. J Pediatr Ophthalmol Strabismus. 1993;30(2):100–5.
2. Sondhi, N., Archer, S.M., Helveston, E.M., Development of normal ocular alignment. J Pediatr Ophthalmol Strabismus. 1988;25(5):210–1.
3. Ponsonby, A.L., Brown, S.A., Kearns, L.S., et al., The association between maternal smoking in pregnancy, other early life characteristics and childhood vision: The Twins Eye Study in Tasmania. Ophthalmic Epidemiol. 2007;14(6):351–9.
4. Cotter, S.A., Varma, R., Tarczy-Hornoch, K., et al., Risk factors associated with childhood strabismus: the multi-ethnic pediatric eye disease and Baltimore pediatric eye disease studies. Ophthalmology. 2011;118(11):2251–61.
5. Staffieri, S.E., “A glint or a squint should make you think!” Towards the earlier diagnosis of retinoblastoma. Chapter 5: Delayed Diagnosis of Retinoblastoma in Victoria. [Dissertation]. Melbourne, Victoria: University of Melbourne; 2019. Available at: http://hdl.handle.net/11343/227062.
6. Haider, S., Qureshi, W., Ali, A., Leukocoria in children. J Pediatr Ophthalmol Strabismus. 2008;45(3):179–80.
7. Robaei, D., Rose, K.A., Kifley, A., et al. Factors associated with childhood strabismus: findings from a population-based study. Ophthalmology. 2006;113(7):1146–53.
8. Hunter, D.G., Ellis, F.J., Prevalence of systemic and ocular disease in infantile exotropia: comparison with infantile esotropia. Ophthalmology. 1999;106(10):1951–6.
9. Williams, A., Hoyt, C.S., Acute comitant esotropia in children with brain tumors. Arch Ophthalmol. 1989;107(3):376–8.
10. Berk, T.A., Oner, H.F., Saatci, O.A., Underlying pathologies in secondary strabismus. Strabismus. 2000;8(2):69–75.
11. Kim, I.G., Park, J.M., Lee, S.J., Factors associated with the direction of ocular deviation in sensory horizontal strabismus and unilateral organic ocular problems. Korean J Ophthalmol. 2012;26(3):199–202.
12. Marshall, J., Gole, G.A., Unilateral leukocoria in off axis flash photographs of normal eyes. Am J Ophthalmol. 2003;135(5):709–11.
13. Sefi-Yurdakul N, Tugcu B. Development of strabismus in children initially diagnosed with pseudostrabismus. Strabismus. 2016:1–4.
14. Staffieri, S.E., Kearns, L.S., Sanfilippo, P.G., et al., Crowd-sourced ontology for photoleukocoria: Identifying common internet search terms for a potentially important pediatric ophthalmic sign. Transl Vis Sci Technol. 2018;7(1):18.
15. Li, J., Coats, D.K., Paysse, E., et al., The detection of simulated retinoblastoma by using red-reflex testing. Pediatrics. 2010;126(1):e202-e7.
16. Donahue, S.P., Nixon, C.N., Section on Ophthalmology AAoP. Visual System Assessment in Infants, Children, and Young Adults by Pediatricians. Pediatrics. 2016;137(1):28–30.
17. Khokhar, S., Jose, C.P., Sihota, R., Midha, N., Unilateral congenital cataract: Clinical profile and presentation. J Pediatr Ophthalmol Strabismus. 2018;55(2):107–12.
18. Abramson, D.H., Beaverson, K., Sangani, P., et al. Screening for retinoblastoma: presenting signs as prognosticators of patient and ocular survival. Pediatrics. 2003;112(6):1248–55.
19. Taylor, R.H., Guidelines for the Management of Strabismus in Childhood 2012. Available at: rcophth.ac.uk/resources-listing/guidelines-for-the-management-of-strabismus-in-childhood/ [accessed 8 Nov 2023].