Population study: Incidence of Congenital Cataracts and Efficacy of Screening Programme

doi:10.21203/rs.3.rs-2082377/v1

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Population study: Incidence of Congenital Cataracts and Efficacy of Screening Programme

https://doi.org/10.21203/rs.3.rs-2082377/v1

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Background

The red reflex test (RRT) is widely used as a screening tool to detect congenital cataract. This study aims to determine the incidence of congenital cataract in Northern Ireland and to evaluate the success of the RRT screening programme.

Methods

Retrospective review of consecutive abnormal red reflex referrals in 2017 and 2018 inclusive. We collected data on the source and timing of referral, diagnostic outcome, visually significant cataract, and surgical intervention. Additionally, data was collected on all cases of confirmed congenital cataract diagnosed in the Regional Paediatric Ophthalmology Service within the same time period.

Results

In the study period, 179 children with suspected red reflex abnormalities were referred. In the same period, thirteen patients were diagnosed with visually significant congenital cataract under one year. Eight (62%) were female and seven (54%) affected both eyes. Only 46% were detected through the screening programme. Three children were above one year of age at the time of diagnosis with sub-optimal outcomes. Six patients were diagnosed with non-visually significant congenital cataract and one juvenile onset were not included. Eight infants diagnosed with lens opacities required surgical intervention. Incidence of visually significant congenital cataract in Northern Ireland was calculated at 2.8 per ten thousand live births per year.

Conclusions

Northern Ireland has a similar incidence of congenital cataract compared to the remainder of the UK. This study highlights that red reflex screening requires further refinement, which can be augmented by pupillary dilatation, to ensure timely diagnosis and improve visual outcomes.

In the UK, the red reflex test (RRT) is used to screen for congenital cataract during the Newborn and Infant Physical Examination (NIPE) within 72hours of birth and at the 6–8-week GP examination (1, 2) (,). Incidence of congenital and infantile cataract, in the first year of life, has been reported to be 2.49 per 10,000 children in the UK and 2.03 per 10,000 in the USA (3, 4). Globally, the incidence can be as high as 15 per 10,000 births which may be attributable to rubella infection (5). Congenital cataract is most commonly isolated with no identifiable cause; however, autosomal dominant inheritance can occur. Congenital cataract can also be associated with a chromosomal abnormalities (e.g. trisomy 21) or occur in association with underlying metabolic conditions (e.g., galactosaemia). The RRT is used in many countries soon after birth to screen for cataract and other ocular anomalies such as retinoblastoma which can be life-threatening and, when detected early, can reduce enucleation rates and preserve visual function (6).

Congenital cataract leads to visual impairment in the form of dense amblyopia secondary to stimulus deprivation. UK management of these cases involves multi-disciplinary expertise including paediatric ophthalmology, orthoptics, optometry, genetics and paediatrics (7). Early detection is paramount in ensuring that these infants receive timely treatment in order to optimise outcomes.

The RRT examination accounts for a small part of the newborn examination which is performed by midwives, paediatricians and general practitioners. The red reflex describes a red-orange hue reflected from the retinal and choroidal blood supply when shining a co-axial light into the eye. Each eye is examined in succession and an abnormal red reflex (ARR) can represent leukocoria, i.e., a white reflex. Asymmetrical, dull, diminished or partial reflexes can also indicate ocular pathology (8). Any opacity disrupting the reflection of light through the patient’s eye can lead to an ARR, including conditions such as congenital cataract, retinoblastoma, glaucoma, astigmatism and other eye conditions (9).

The challenge faced by paediatric ophthalmology units is twofold. Firstly, that posed by late presentation of ARR patients and secondly, high rates of false positives. This has prompted a search for alternatives to the RRT to detect congenital cataract and retinoblastoma. The largest review, a recent meta-analysis of five studies including 8 713 patients showed that red reflex screening without pupillary dilatation has a low sensitivity (7.5%) and a high specificity (97.5%) (10). Therefore, when an ARR is detected, less than 1 in 10 indicate true pathology given large numbers of false negatives, and a normal red reflex often rules out ocular pathology. Ideally, a screening test has a high sensitivity; however, given the severity and rarity of retinoblastoma and risk to lifelong visual impairment with undetected cataract many argue a lower sensitivity is acceptable.

We performed a retrospective study of patients referred with red reflex anomalies and in parallel collected data on all patients diagnosed with lens opacities over a two-year period. Referrer details, timing of referral, time to reach tertiary paediatric ophthalmology clinic, management and outcomes were determined. Our aim was to determine the sensitivity and specificity of the NIPE red reflex examination and to estimate the incidence of congenital cataract in Northern Ireland.

We performed a retrospective case note review of patient referrals to the Royal Victoria Hospital, Belfast, the tertiary referral centre for paediatric ophthalmology in Northern Ireland, for two complete years, 2017 and 2018. Full approval was obtained from the Belfast Health and Social Care Trust (BHSCT) Standards, Quality and Audit department. Two sets of data were collected. The first dataset consisted of patients referred with suspected red reflex abnormalities and included details of the referrer, age of infant at time of referral, and the clinical outcome of the referral. The second dataset was collected for all children diagnosed with congenital cataracts in Northern Ireland for the study period. A clinical diagnosis of congenital cataract was used as in previous incidence studies (3). These were subsequently analysed to determine those referred after being identified by the red reflex screening program or due to other referral pathways. These patients were analyzed to determine referral source, age at referral, and the clinical outcome. Patient information was managed in accordance with the BHSCT guidance on data protection.

Between 1st January 2017 and 31st December 2018, 179 patients were referred with possible red reflex abnormalities of which 99 (55%) were male and 80 were female (45%). Of these, 31 were over one year of age highlighting the ongoing use of the RRT beyond the screening programme. There were 45 997 live births in Northern Ireland during this time as reported by the Northern Ireland Research and Statistics Agency (NISRA) (11). Therefore, a very small proportion of the newborn population were referred with suspected red reflex abnormalities to our unit. A total of 13 infants up to one year of age were diagnosed with visually significant congenital cataract (including those not detected by red reflex screening) during the same period which provides an incidence of 2.8 per ten thousand per year.

There were 3 cases of congenital cataract detected after one year of age. Two of these were idiopathic posterior polar in nature, one required surgery and the other was managed with spectacle correction and patching for amblyopia. The remaining case was bilateral, had a strong family history and was associated with a PEX6 mutation.

For ARR referrals, age at time of referral was younger than 6 weeks of age in 36% (n = 64) of cases; however, a significant 29% (n = 52) of patients were referred after 12 weeks of age (Table 1). Most referrals came from GPs (51%, n = 92) and paediatricians (34%, n = 60) and other referrals arose from eye casualty (n = 8), optometrists (n = 8), ophthalmologists (n = 4), health visitors (n = 3), orthoptists (n = 3) and midwives (n = 1). Following referral, 88% of patients were seen in paediatric ophthalmology clinic within 4 weeks and 98% were seen by 6weeks.

A high proportion of patients referred (79.9%, n = 143) had a normal ocular examination. Following ARR referral, thirteen patients were found to have cataract, of which only six were visually significant and four required surgical intervention. Additionally, 20 patients (11.2%) had other clinical findings including anterior segment dysgenesis, refractive error, retinal haemorrhage, trauma, strabismus, nasolacrimal duct obstruction and retinoblastoma (Table 2). It could be argued that thirty-three (18.4%) patients referred warranted review in the tertiary centre. Three patients did not attend and no further follow up information is available at the time of writing.

Clinical outcomes were analysed and 73% (n = 131) of infants were discharged without follow up, 20% (n = 35) had a subsequent ophthalmology review, 4% (n = 7) were referred for local orthoptic follow up and 3% (n = 6) were listed for surgery.

We attempted to determine the validity of the red reflex test by analysing the number of patients who were found to have lens opacity in the same period. In total, sixteen patients were diagnosed with visually significant congenital cataract, 8 bilateral, 4 right and 4 left. Six were detected by the RRT, three during neonatal screening, two at the 6-to-8-week screen and one at 33weeks of age. A case of Juvenile onset and six non-visually significant lens opacities were excluded. Beyond the RRT, infants subsequently diagnosed with lens opacity were referred with strabismus (n = 1), not fixing and following (n = 2), work up of an infant with suspected syndrome (n = 1), family history of cataract (n = 2), known diagnosis of galactosaemia (n = 2), pupil/iris anomaly (n = 1) and after parents noticed a problem (n = 1).

Sensitivity was calculated at 46.1% for the RRT detecting visually significant cataract (increasing to 65.0% including non-visually significant cataract) assuming all infants with red reflex anomalies were referred to our unit. It is possible that a small number will also have been referred to the one other district general hospital with paediatric ophthalmology in Northern Ireland, which would cause a slight underestimation of the true value. As with previous studies, the specificity is high for red reflex screening in Northern Ireland (99.6%). This assumes all live births are screened as per UK government guidance.

The RRT is the only screening tool currently in use to detect congenital cataract, a rare treatable cause of visual impairment where timely management can result in near normal vision. A recent review of the paediatric population of Northern Ireland found on average one patient per year is registered visually impaired due to congenital cataracts which could be avoidable with early detection (12). Northern Ireland has an ideal population for epidemiological studies due to its higher rate of immigration to emigration and the incidence of congenital cataract was previously unknown. We estimate an incidence of 2.8 cases of congenital cataract per ten thousand live births per year which is similar to estimates for the UK as a whole (3).

We estimate a low sensitivity (46.1%) and a high specificity (99.6%) for red reflex screening as in previous cross-sectional and retrospective studies (10). Other studies, however, have shown a much higher sensitivity (99.6%) for anterior anomalies with a much lower sensitivity (4.1%) for posterior segment pathology (13). Given, the red reflex test detected other pathology including one case of retinoblastoma the sensitivity is likely to be higher for all eye problems. We acknowledge our figure may underestimate the sensitivity of the red reflex check for congenital cataract given the possibility that some small, off axis lens opacities not requiring surgical intervention may have been managed elsewhere and not referred to the regional centre.

There is a growing global consensus that timing of surgery for unilateral cataract surgery is optimal between 6 and 8 weeks. Surgery before 4 weeks is associated with a higher risk of post-operative glaucoma and beyond 8 weeks increases the risk of amblyopia. This narrow treatment window highlights the necessity for urgent referral of suspected cases to be made to Paediatric Ophthalmology departments prior to 8 weeks, if not sooner. Delayed diagnosis will almost certainly lead to amblyopia. It is therefore a major concern that only half of visually significant cataract were detected within the time critical 6-week period and 36% of all queried abnormal red reflex referrals were prior to 6 weeks post gestational age. One possible factor is that the 6-8week GP examination visit is often carried out around 2months of age to coincide with the infant’s first immunisations coinciding with a peak in referral between 8–12 weeks (Table 1).

Infants in neonatal care units may not receive their baby check until discharge which in some cases may occur after 8 weeks post gestational age. Although neonates undergoing ROP screening are likely to be picked up, those not meeting criteria for screening may not get a red reflex check until well into their admission. For this reason, in our unit, we have advised a check of the red reflex sooner. Similarly, the UK government website suggests screening when the infant is well enough (14).

The red reflex can appear diminished, yellow or bilaterally pale in black and minority ethnic (BME) infants and is a common reason for unwarranted referral. To minimise these referrals, many suggest referrers reassess with dilating drops such as cyclopentolate 0.5% or Tropicamide 0.5% (15). In support, a simulated model pupillary dilatation has been shown to increase sensitivity (16). Furthermore, incorrectly detecting a normal reflex at screening is one possible reason for delayed diagnosis of congenital cataract leading to irreversible sight loss. In small un-dilated pupils, small lens opacities are easily missed in an otherwise normal red reflex especially. We too, would recommend using dilating drops such as tropicamide 0.5% or cyclopentolate 0.5% one drop to each eye which can be repeated for dark brown eyes. Drops can be instilled prior to performing the other elements of the newborn physical examination to allow time for the pupils to dilate. This represents a low cost, safe and efficient method to help reduce inappropriate referrals and improve detection rates.

Alternatives to the red reflex examination by direct ophthalmoscope are being considered with smartphone-based screening tools likely to provide the most promising alternative. In a recent pilot study, Infra-red reflex imaging implementing a smart phone adaptor was shown to improve detection (17). Two free apps, MDEyeCare and CRADLE have been developed to diagnose leukocoria (18). CRADLE allows users to download the app and analyse the photos stored on their device; however, this tool is likely to lead to high rates of false positives (19). A small pilot by the author (EP) found the app to detect many photos with normal light reflections which could give parents unwanted anxiety. Many referrals have historically come from flash photographs taken by parents who have seen public safety campaigns on the white reflex; however, the use of mobile phone photography has rapidly replaced the flash camera. The use of smartphones as a screening tool could increase referral rates for suspected leukocoria due to artefact or where the optic nerve is inadvertently imaged (20) which is particularly problematic with off-axis photographs (21, 22). On the other hand, modern mobile phones often automatically eliminate the red reflex leading to missed opportunities. It was commonplace, in the not-too-distant past, to digitally remove unwanted red reflexes from photographs which lead to some parents blacking out abnormal white reflexes delaying diagnosis (23).

Given the sophistication of mobile phone devices and the emergence of artificial intelligence in ophthalmology and healthcare it seems highly possible that photographs taken on smart phones could be analysed by internal software which detects white reflexes. There has been some promising work looking at colimetric values of red reflexes in photographs of infants with confirmed retinoblastoma compared to controls. A detailed longitudinal analysis of one infant’s photographs showed that leukocoria was present as early as 12–35 days which could have led to earlier detection. Leukocoria seen in retinoblastoma is most frequently picked up by parents (up to 80%), however, given the greater eye salvage and retained acuity in those screened due to a positive family history leukocoria could be considered a late sign (24).

We must accept that the RRT will not detect every ocular pathology. A group from China has attempted to estimate the true prevalence of congenital ocular findings by performing a detailed ophthalmic examination on over 3000 healthy newborns including Retcam fundus imaging (25). Perhaps the most striking finding was the incidence of retinal haemorrhage, and the authors feel further work is justified in determining the associated risk of developing amblyopia. Further, the detection of an early retinoblastoma will no doubt have improved the long-term visual outcomes and eye salvage for that infant. There is no intention by the authors to set this examination standard for screening, but it provides an interesting perspective on what could be achieved with unlimited resources.

Limitations

Northern Ireland has only one regional unit for paediatric ophthalmic surgery in under 1-year old, so all operable cataracts will have been identified. However, there is one other unit, Altenagelvin Hospital, where a small number of patients could have been referred so this study may not have collected all red reflex referrals. Therefore, the authors advise to allow for some underestimation on the referral numbers for the region.

In this study, we estimated the incidence of congenital cataract in Northern Ireland. As compared to similar studies the red reflex test has a low sensitivity for detecting congenital cataract, however, in this instance a low sensitivity is an essential compromise to minimize missed cases. In the first instance simple measures such as routine pupillary dilation could be added to the screening examination which may help detect cataract and retinoblastoma. At our unit we have developed an educational video for healthcare professionals to provide further training on the red reflex examination at induction for trainee pediatricians, midwives and GPs to help minimise falsely negative RRTs and to instigate prompt referral. Given the wide access to smart phones we wonder if it is time to move away from the direct ophthalmoscope and endorse free apps, however, further refinement of these technologies is needed. Virtual appointments could be utilised, and abnormal images could be sent for review by an ophthalmologist prioritizing the greatest need in face-to-face clinics. Further work on validation of these apps as screening tools is needed but they offer an interesting and exciting option for the future to help detect preventable causes of blindness in our newborns.

Competing interest:

The authors declare no conflict of interest or financial disclosures.

Conflict of Interests

The authors declare no conflict of interest or financial disclosures.

Funding

No grants or funding were acquired for the present work

Author Contribution Statement

EP wrote the manuscript, extracted and analysed data, interpreted the results, and reviewed the literature for discussion. RT contributed to data collection, analysis and writing the report. KS contributed to data collection, analysis and writing the report. SG contributed to data collection. EM contributed to data collection and to the writing of the report.

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Tables 1 and 2 are available in the Supplementary Files section.

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Table1.xlsx
Table 1. Timing of abnormal red reflex referrals Table 1. Categorical data showing age of patients at time of referral and at first visit to the ophthalmology department.
Table2.xlsx
Table 2. Diagnosis of patients referred with red reflex abnormalities Table 2. Diagnosis of patients referred with red reflex abnormalities. NLDO - nasolacrimal duct obstruction, DNA - Did not attend

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Population study: Incidence of Congenital Cataracts and Efficacy of Screening Programme

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