The FASD Eye Code: a complementary diagnostic tool in fetal alcohol spectrum disorders

Introduction

Since the recognition of fetal alcohol syndrome (FAS), alcohol has been shown to produce a wide spectrum of physical, neurological, cognitive and ophthalmological aberrations, now known as fetal alcohol spectrum disorders (FASD).1–15 The prototypical features of FAS are small palpebral fissures, a thin upper lip, a smooth philtrum, growth restrictions and central nervous system abnormalities (figure 1).1–3 8 16–18 Although previous studies have shown that small palpebral fissures are not the only ophthalmological features occurring frequently in children with FASD,9 11 13 19 the role of ophthalmological assessment in the work-up of FASD may be underestimated.

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Alcohol use during pregnancy is a public health problem worldwide. A meta-analysis estimated that over 100 000 children around the world are born with FAS every year.20 The incorporation of the diagnosis ‘neurodevelopmental disorder – prenatally exposed’ into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition is a recognition of the association between alcohol exposure and behavioural and cognitive deficits. Within this wider spectrum of prenatal alcohol exposure (PAE), there is less agreement on what constitutes an alcohol-related aetiological diagnosis,21 22 and several sets of diagnostic criteria are used around the world to diagnose FASD. However, the key features of FAS in each set of criteria are the same: growth deficiency, facial dysmorphology and neurobehavioural impairment (figure 1).2 3 16–18

Ophthalmological findings, such as subnormal visual acuity, refractive errors, motility disorders, strabismus, and abnormalities of the retinal vessels and optic head, are frequently found in individuals with FASD, but these ophthalmological findings are also found in children with, for example, attention deficit/hyperactivity disorder (ADHD), as well as prematurely born children.23 24 On the other hand, both ADHD and prematurity are frequently found in children diagnosed with FASD.4 5 8 To what extent this co-occurrence is caused by confounding alcohol exposure is unknown, and clinically discriminating between alcohol exposure and other factors remains a challenge. Strabismus and refractive errors may cause amblyopia and visual impairment, which are treatable if found in early childhood, but if not treated may present additional problems for already affected individuals. Moreover, other groups with neurodevelopmental syndromes and genetic disorders may also present with similar ophthalmological abnormalities, although other clinical symptoms are usually present as well.

The medical diagnostic process is probabilistic in nature.25 Arriving at a seemingly dichotomous ‘yes or no’ answer to a diagnosis is guided by a probabilistic weighing of history, findings and tests, where the overarching question is: ‘What is the probability that the patient has this diagnosis, given the information and results?’ In this process, information and tests unspecific to the diagnosis in question help to adjust the probabilities of the diagnosis in a useful way. Analogous to supportive laboratory investigations, a complementary eye diagnostic tool could provide independent verification for clinicians, thus strengthening and helping FASD diagnostics. However, to be of use, findings must differentiate between FASD and children with other conditions presenting with similar symptoms. It should also be considered that anthropometric criteria are less evident in adulthood, while cognitive impairment and psychiatric morbidity are more evident in adults with FASD.4 5 26 27

The aims of this study were threefold: first, to develop and propose a complementary and easy-to-use tool based on ophthalmological findings to support an FASD diagnosis; second, to validate the FASD Eye Code’s capacity to discriminate FASD eye findings from prematurity, growth restriction and ADHD without diagnosed FASD; and third, to test the tool in long-term follow-up of individuals with FASD from childhood to young adulthood. In addition, the tool should be useful both in eye clinics and elsewhere, allowing use in outreach and epidemiological surveys of FASD in different communities, while simultaneously identifying treatable deficits requiring management no matter what the cause.

Materials and methods

Developing the FASD Eye Code

Based on the accrued evidence of ophthalmological studies on FASD and our own clinical experience,4 5 9–14 19 four of the most commonly affected ophthalmological features in children with FASD were chosen to create the four categories constituting the FASD Eye Code. The four categories are (A) best corrected visual acuity (BCVA), (B) refraction, (C) strabismus and binocular function, and (D) ocular structural abnormalities. By design, the selected tests are easy to use both in the clinic and on the field (figure 2).

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Figure 2

The FASD Eye Code categories: (A) best corrected visual acuity, (B) refraction, (C) strabismus and binocular function (drawing by Eva Aring), and (D) ocular structural abnormalities. FASD, fetal alcohol spectrum disorder.

Among the chosen ophthalmological features, two are structural measures (refraction and ocular structural abnormalities) and two are functional tests (BCVA and strabismus/binocular function). The functional measurements represent both afferent and efferent functions. Normal scores in each category are based on known levels in a normal paediatric population,28 29 and the maximal scores are based on affected ophthalmological features well characterised in children with FASD.9–14 30 31 We have excluded palpebral fissure length in the FASD Eye Code since this variable is included in all FASD diagnostic criteria previously mentioned.2 3 16–18

The FASD Eye Code: long-term follow-up

In total, 30 out of the 37 young adults (81%) with FASD (FAS=19, PFAS=6, ARND=5) participated in a follow-up investigation at a mean age of 23 years (range 19–28 years). Six young adults declined to participate and one discontinued the study (figure 3).12

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Figure 3

Individual FASD Eye Code total score in 30 subjects diagnosed with FASD, in both childhood and early adulthood. ARND, alcohol-related neurodevelopmental disorder; FAS, fetal alcohol syndrome; FASD, fetal alcohol spectrum disorders; PFAS, partial FAS.

Results

Table 1 shows the median (IQR) FASD Eye Code score of the four categories (BCVA, refraction, strabismus and binocular function, and ocular structural abnormalities) in all groups (FASD, age-matched and sex-matched controls, ADHD, MLP and SRS) and FASD subgroups (FAS, PFAS and ARND), as well as the total median scores (range, IQR) for all groups.

Figure 3 shows the individual total score, in both childhood and early adulthood, for the 30 subjects diagnosed with FASD.

A cut-off total score of ≥10 was chosen to represent an FASD diagnosis based on the total sample (this score was obtained by 16 of 37 participants with FASD, 6 of 33 with ADHD, 3 of 57 with MLP, 3 of 16 with SRS and 0 of 65 controls). Thus, an FASD Eye Code cut-off score of ≥10 has 100% specificity and 43% sensitivity, with an area under the curve (AUC) of 0.87 (95% CI 0.80 to 0.95), in discriminating between FASD and healthy controls. When comparing FASD versus controls, ADHD and MLP, the specificity was 94% and the sensitivity was 43% (AUC=0.78; 95% CI 0.69 to 0.87). This result corresponds to a positive likelihood ratio of 7.5. If comparing FASD versus all groups, the AUC was 0.76 (95% CI 0.67 to 0.86). When comparing FASD versus ADHD, the AUC was 0.66 (95% CI 0.53 to 0.78); for FASD versus MLP, the AUC was 0.75 (95% CI 0.64 to 0.86); and for FASD versus SRS, the AUC was 0.60 (95% CI 0.45 to 0.75). The subgroup FAS versus controls showed the highest AUC value of 0.92 (95% CI 0.85 to 1.0), and for a cut-off score of ≥10 the specificity was 100% and the sensitivity was 62%. A cut-off score of ≥9 showed a specificity of 98% and a sensitivity of 57% for FASD versus healthy controls, corresponding to a positive likelihood ratio of 36.9. Tables of diagnostic indices for ROC curves (cut-off, sensitivity, specificity, accuracy, likelihood ratio) are provided in (figure 4A–G and online supplemental file 3).

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Discussion

We created and evaluated a new complementary diagnostic tool, the FASD Eye Code, by comparing children with FASD, age-matched and sex-matched healthy controls, and groups of individuals with ADHD, MLP and SRS. Long-term follow-up (re-examination) of individuals with FASD in young adulthood indicated the persistence of childhood findings. Our results show that the FASD Eye Code can distinguish among different FASD subgroups and discriminate between different patient groups with similar ophthalmological problems.23 24 33 The FASD Eye Code shows better specificity than sensitivity for FASD, with a total score of ≥10 having an increasing likelihood of ruling in an FASD diagnosis. In addition, our results are of clinical importance and require management no matter what the cause is, and the findings may offer useful clues to potential aetiology. To the best of our knowledge, this is the first ophthalmological tool developed to support an FASD diagnosis in both childhood and young adulthood.

The wide range of scores among children with FASD is not surprising as it reflects the range of eye findings associated with PAE during the different stages of development of the fetus, and in some cases eye findings may be due to PAE without rising to a FASD diagnosis. Thus, children who scored ≥10 were most commonly those with fully developed FAS, and no one among the controls scored 10 or above. Among children with SRS, 2 of 16 children scored 11 and 1 scored 13. Unlike the other evaluated groups (ADHD, MLP and controls), all children with SRS showed growth deficits both prenatally and at the time of assessment, which are among the hallmarks of an FASD diagnosis. However, children with SRS have other symptoms and signs, including ophthalmological findings,33 which indicate an SRS rather than an FASD diagnosis. The same is mostly true when differentiating FASD from other syndromes.12 However, genetic testing could also be valuable in these cases as a co-occurrence with PAE is possible.

Six children in the ADHD group (children without diagnosed FASD nor born preterm/SGA) were noted to have an FASD Eye Code total score ≥10; three of these children with ADHD had a score of 11 or above. This may be misclassification due to confounding from undiagnosed PAE and undiagnosed FASD, or due to neurodevelopmental afflictions of other aetiology. The criteria for ADHD, a symptom-based diagnosis, were met by the majority of children/young adults with an aetiological diagnosis of FASD.5 8

Visual acuity and refraction are age-dependent,28 which must be considered when diagnosing different individuals and age groups. No gender differences between the ophthalmological variables used in the code have been shown in controls.28 However, refraction and strabismus may have ethnicity-based variation.35 Thus, our values are suitable for Caucasian children between 4 and 15 years of age. Since the typical facial feature of FAS seems to diminish with age,27 we tested whether the FASD Eye Code could still be applicable in young adults with FASD. Out of 37 individuals, 30 were assessed in both childhood and young adulthood,12 showing no significant differences in the FASD Eye Code total score. Since refraction differs in different age groups, myopia was also evaluated in the young adult group, with a cut-off of ≥2.0 dioptre (D) spherical equivalent (SE). However, no difference was noted in the FASD Eye Code total median score when comparing the two different cut-offs (myopia ≥1 D SE vs ≥2 D SE), as individuals with FASD more often have astigmatism or anisometropia, which gives a higher score in the refraction category.