Mother-infant interactions with infants with congenital visual impairment and associations with longitudinal outcomes in cognition and language.

BACKGROUND: This study investigated mother-infant interactions, including maternal maintaining of infant attentional focus and sensitivity, with infants with congenital severe and profound visual impairment (VI) and the association with developmental trajectories from one to three years. METHOD: Fifty-five infants and mothers were video-recorded playing together with a standard set of toys at Time 1 (T1) mean age 12.95 months (8.13-17.05 months). Maintain was categorized as the mother following and maintaining the child's focus, and Sensitivity, the mother's responsiveness and contingency to infant behaviour. Vision level was measured using the Near Detection Scale. Cognition and language were measured at T1, 12 months later (T2) and 24 months later (T3) using the Reynell-Zinkin Scales. RESULTS: Cross-sectional analyses showed that mothers of infants with severe VI (basic form vision) produced higher rates of Maintain compared to those with children with profound VI (light perception at best). Linear mixed-effects models examining developmental progression from T1 to T3 (controlling for vision level) showed an average increase of 5 DQ points (CI 95%: 1.03-9.08) in verbal comprehension for higher Sensitivity. No significant findings were found for Maintain. CONCLUSIONS: The findings suggest that mother-infant interactions (maternal Maintain) are associated with level of vision at infancy, but only maternal Sensitivity has a long-term positive association with advances in verbal comprehension from infancy to about three years. They highlight the need for incorporating strategies related to parent-infant interactions, including increased sensitivity, into early intervention for children with visual impairment.

Detection vision development in infants and toddlers with congenital vision disorders and profound-severe visual impairment.

AIM: To investigate detection vision development in infants and toddlers with congenital disorders of the peripheral visual system (CDPVS) and severe to profound visual impairment (SVI/PVI). METHOD: This was a longitudinal observational investigation of a cohort of infants with CDPVS (entry age 8-16mo) followed up 12 months later. Detection vision (Near Detection Scale [NDS]) and resolution acuity (Keeler Acuity Cards [KAC]) were assessed at each time point. Relationships between detection vision, resolution acuity, and age were investigated. RESULTS: The study cohort comprised 80 children (39 females, 41 males), mean age 13 months (Time 1) and 26 months (Time 2); 22 (27.5%) with PVI (light perception at best) and 58 (72.5%) with SVI (basic 'form' vision) at Time 1. All children achieved a measure with the NDS, however only 35 per cent and 56 per cent at Time 1 and Time 2 respectively did so on KAC. Those with PVI at Time 1 showed no further improvement at Time 2, but 87 per cent of children with SVI showed improvement in vision. The median change in NDS score was 1.0 (range 1-7, SD 1.68). INTERPRETATION: Vision development continues after 12 months of age in many toddlers if they have basic 'form' vision. A measure of detection vision is feasible in very young children when resolution acuity measurement is not achievable. WHAT THIS PAPER ADDS: The Near Detection Scale (NDS) can measure low levels of vision when acuity is not otherwise measurable. Vision can improve in toddlers with severe visual impairment who have some 'form' vision. Infants with light perception at best by 12 months are unlikely to show improvement in vision. There is a moderate negative relationship between the NDS and resolution acuity results.

Home-based early intervention in infants and young children with visual impairment using the Developmental Journal: longitudinal cohort study.

AIM: To investigate the effects of home-based early intervention in children with severe visual impairment (SVI) using the Developmental Journal for babies and young children with visual impairment (DJVI). METHOD: A longitudinal observational study was undertaken with a national cohort (OPTIMUM) of infants with congenital disorders of the peripheral visual system (CDPVS) and profound-SVI; and followed up after 12 months and 24 months. Intervention was categorized according to the practitioner diary records of their usual practice over 12 months from baseline comparing those receiving the DJVI and those receiving 'Other Support'. Outcome measures of cognition and language, behaviour difficulties, parenting stress, and satisfaction with parent-practitioner partnership were collected. RESULTS: In the 54 children (26 males, 28 females, baseline mean age 13.5mo, SD 2.3mo, range 8-17mo) with 'total' CDPVS (including 16 'complex' and 38 'simple' with or without known brain disorder respectively), linear mixed effects pointed towards acceleration in sensorimotor understanding and expressive language especially in the 'simple' subsample (11.72 developmental quotient, 95% confidence interval -1.17 to 24.61, p>0.05) in those receiving the DJVI. Vision level also predicted outcomes (p<0.05). The DJVI group showed improvements in behavioural withdrawal (η2 =0.20, p=0.02, 'simple') and parenting stress (d=0.78, d=0.92, p=0.02 total and 'simple' respectively) and perceived practitioner-parent relationship (η2 =0.16, p=0.01). INTERPRETATION: Infants and young children with visual impairment receiving home-based early intervention using the DJVI with a structured developmental approach had better outcomes than those receiving 'other' home-based early interventions. Moderate to large effect improvements were found in child cognition and language, behaviour and parenting stress and the perceived practitioner-parent relationship, although cognition did not reach 5% significance level. WHAT THIS PAPER ADDS: Early intervention using the Developmental Journal for babies and young children with visual impairment was associated with enhanced developmental outcomes compared to other approaches. Improvements were also found in child behaviour, parenting stress, and perceived parent practitioner outcomes. Type and complexity of visual impairment also influenced outcomes.

INTERVENCIÓN TEMPRANA DOMICILIARIA EN LACTANTES Y NIÑOS PEQUEÑOS CON DISCAPACIDAD VISUAL USANDO EL DIARIO DE DESARROLLO: ESTUDIO LONGITUDINAL DE COHORTE: OBJETIVO: Investigar los efectos de la intervención temprana en el hogar en niños con discapacidad visual grave utilizando el Diario de Desarrollo para bebés y niños pequeños con discapacidad visual (DJVI). MÉTODO: Se realizó un estudio observacional longitudinal con una cohorte nacional (OPTIMUM) de bebés con trastornos congénitos del sistema visual periférico (CDPVS) y discapacidad visual profunda-severa; y seguimiento después de 12 meses y 24 meses. La intervención se categorizó de acuerdo con los registros del diario de desarrollo del médico en su práctica habitual más de 12 meses desde el inicio, comparando los que recibieron el DJVI y los que recibieron "otro apoyo". Se recopilaron las medidas de resultado de la cognición y el lenguaje, las dificultades de comportamiento, el estrés de los padres y la satisfacción con la asociación entre padres y profesionales. RESULTADOS: En los 54 niños (26 varones, 28 mujeres, edad media de referencia 13,5 meses, DS 2,3 meses, rango 8-17 meses) con CDPVS 'total' (incluidos 16 'complejo' y 38 'simple' con o sin trastorno cerebral conocido respectivamente), los efectos mixtos lineales apuntan hacia la aceleración en la comprensión sensoriomotora y el lenguaje expresivo, especialmente en la submuestra "simple" (cociente de desarrollo 11,72, intervalo de confianza del 95% -1,17 a 24,61, p>0,05) en los que recibieron el DJVI. El nivel de visión también predijo resultados (p <0,05). El grupo DJVI mostró mejoras en la abstinencia conductual (η2 =0,20, p=0,02, 'simple') y el estrés parental (d=0,78 − d=0,92, p=0,02 total y 'simple' respectivamente) y la relación percibida entre el médico y el padre (η2 =0,16, p=0,01). INTERPRETACIÓN: Los bebés y niños pequeños con discapacidad visual que recibieron una intervención temprana en el hogar utilizando el DJVI, con un enfoque de desarrollo estructurado, tuvieron mejores resultados que los que recibieron "otras" intervenciones tempranas en el hogar. Se encontraron mejoras de efecto moderado a grande en la cognición infantil y el lenguaje, el comportamiento y el estrés parental y la relación percibida entre el médico y el padre, aunque la cognición no alcanzó el nivel de significación del 5%.

INTERVENÇÃO PRECOCE DOMICILIAR EM LACTENTES E CRIANÇAS JOVENS COM DEFICIÊNCIA VISUAL USANDO O DEVELOPMENTAL JOURNAL: ESTUDO DE COORTE LONGITUDINAL: OBJETIVO: Investigar os efeitos da intervenção precoce domiciliar em crianças com deficiência visual severa usando o Developmental Journal para lactentes e crianças jovens com deficiência visual (DJDV). METODO: Um estudo observacional longitudinal foi realizado com uma coorte nacional (OPTIMUM) de crianças com distúrbios congênitos do sistema visual periférico (DCSVP) e deficiência visual grave-profunda, estes foram acompanhados após 12 meses e 24 meses. A intervenção foi categorizada de acordo com os registros diários do profissional de sua prática habitual ao longo de 12 meses, a partir de uma linha de base, comparando aqueles que receberam a DJDV e os que receberam "outro suporte". Resultados dos testes de cognição e linguagem, dificuldades de comportamento, estresse parental e satisfação com a parceria entre pais e profissionais, foram coletados. RESULTADOS: Nas 54 crianças (26 do sexo masculino e 28 do feminino, média de idade na linha de base de 13,5 meses; DP 2,3 meses; variação de 8 a 17 meses) com DCSVP total (incluindo 16 'complexos' e 38 'simples' com ou sem distúrbio cerebral conhecido, respectivamente), efeitos mistos lineares apontaram para um avanço na compreensão sensório-motora e de linguagem expressiva, especialmente, no subgrupo 'simples' (11,72 quociente de desenvolvimento, IC 95% -1,17 a 24,61; p>0,05) naqueles que receberam o DJDV. Nível visual também foi preditivo dos desfechos (p<0,05). O grupo DJDV apresentou melhora no comportamento de retraimento social (η2 =0,20; p=0,02; 'simples'), no estresse parental (d=0,78 − d=0,92; p=0,02 total e 'simples', respectivamente) e na percepção do relacionamento profissional-pais (η2 =0,16; p=0,01). INTERPRETAÇÃO: Lactentes e crianças jovens com deficiência visual que recebem intervenção domiciliar precoce usando a DJVI com uma abordagem de desenvolvimento estruturado tiveram resultados melhores do que aqueles que receberam "outras" intervenções precoces em casa. Melhorias com efeito de moderado a grande foram encontradas na cognição e linguagem, no comportamento infantil e estresse parental, e no relacionamento percebido entre pais e profissionais, embora a cognição não tenha alcançado nível de significância de 5%.

Parenting stress, anxiety, and depression in mothers with visually impaired infants: a cross-sectional and longitudinal cohort analysis.

AIM: This study examined cross-sectional and longitudinal patterns of parenting stress, adult anxiety, and depression in mothers of children with profound or severe visual impairment (PVI or SVI) at 1 year and 2 years of age. METHOD: Mothers of a national longitudinal cohort (OPTIMUM Project) of infants with congenital disorders of the peripheral visual system and PVI (light perception at best) or SVI (basic 'form' vision of non-light reflecting objects) participated. Infant age at baseline (T1 ) was 8 to 16 months. Mothers completed the Parenting Stress Index - Short Form and the Hospital Anxiety and Depression Scale at T1 (n=79) and at follow-up 12 months later (T2 ) (n=73). RESULTS: Mothers of the total group had higher parenting stress levels (34.6% in clinical range) than community normative data at T1 (p=0.017). Mothers of infants in the PVI subgroup had elevated stress at T1 (p=0.014) and T2 (p=0.009). The PVI subgroup was also elevated in the Difficult Child subscale at T2 (p=0.001). Within-sample differences in parenting stress between the visual impairment subgroups were found at T2 only: the PVI subgroup scored higher than the SVI subgroup (p=0.029). Adult anxiety and depression in the total group were not elevated compared with community normative data at T1 and T2 ; however, higher parenting stress was related to raised adult anxiety and depression levels at T1 and T2 (p=0.001). Regression analysis found parenting stress and lower child vision level (T1 ) predicted parenting stress (T2 ) (p=0.001; 42% variance). INTERPRETATION: Mothers of 1-year-old infants with visual impairment showed raised risk for parenting stress, which continued to be elevated for children with PVI and those perceived as 'difficult' at 2 years. This was also a psychological risk, with greater adult anxiety and depression in those mothers with raised parenting stress. The clinical significance is that identification of parenting stress and targeted parenting, and behavioural support of the child in the first years of life is highly indicated. WHAT THIS PAPER ADDS: Mothers of infants with visual impairment are at increased risk of parenting stress. Parenting stress was higher in mothers of children with profound visual impairment than those with severe visual impairment. High levels of parenting stress and lower infant vision at 1 year of age predicted higher parenting stress at 2 years of age.

Functional vision and cognition in infants with congenital disorders of the peripheral visual system.

AIM: To investigate how vision relates to early development by studying vision and cognition in a national cohort of 1-year-old infants with congenital disorders of the peripheral visual system and visual impairment. METHOD: This was a cross-sectional observational investigation of a nationally recruited cohort of infants with 'simple' and 'complex' congenital disorders of the peripheral visual system. Entry age was 8 to 16 months. Vision level (Near Detection Scale) and non-verbal cognition (sensorimotor understanding, Reynell Zinkin Scales) were assessed. Parents completed demographic questionnaires. RESULTS: Of 90 infants (49 males, 41 females; mean 13mo, standard deviation [SD] 2.5mo; range 7-17mo); 25 (28%) had profound visual impairment (light perception at best) and 65 (72%) had severe visual impairment (basic 'form' vision). The Near Detection Scale correlated significantly with sensorimotor understanding developmental quotients in the 'total', 'simple', and 'complex' groups (all p<0.001). Age and vision accounted for 48% of sensorimotor understanding variance. Infants with profound visual impairment, especially in the 'complex' group with congenital disorders of the peripheral visual system with known brain involvement, showed the greatest cognitive delay. INTERPRETATION: Lack of vision is associated with delayed early-object manipulative abilities and concepts; 'form' vision appeared to support early developmental advance. This paper provides baseline characteristics for cross-sectional and longitudinal follow-up investigations in progress. A methodological strength of the study was the representativeness of the cohort according to national epidemiological and population census data.

Fifteen-minute consultation-the child with a developmental disability: is there an ocular or visual abnormality?

OBJECTIVE: To present a structured approach for an outpatient consultation for a child with developmental disability who may have an ocular or visual disorder. METHOD: Review of relevant literature and description of the approach to ocular and visual assessment which could be used by any paediatrician. CONCLUSION: A systematic approach to history, observation and examination of a child with a developmental disability will assist in identifying a possible visual problem. A structured referral letter will ensure that the child will receive the most appropriate assessment to clarify the problem and appropriate management in the eye clinic.

Treatment of neonatal sepsis with intravenous immune globulin.

BACKGROUND: Neonatal sepsis is a major cause of death and complications despite antibiotic treatment. Effective adjunctive treatments are needed. Newborn infants are relatively deficient in endogenous immunoglobulin. Meta-analyses of trials of intravenous immune globulin for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality. METHODS: At 113 hospitals in nine countries, we enrolled 3493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either polyvalent IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart. The primary outcome was death or major disability at the age of 2 years. RESULTS: There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1759 infants (39.0%) who received intravenous immune globulin and in 677 of 1734 infants (39.0%) who received placebo (relative risk, 1.00; 95% confidence interval, 0.92 to 1.08). Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or nonmajor disability or of adverse events. CONCLUSIONS: Therapy with intravenous immune globulin had no effect on the outcomes of suspected or proven neonatal sepsis.

Inter-rater reliability and agreement of the General Movement Assessment and Motor Optimality Score-Revised in a large population-based sample.

BACKGROUND: Prechtl's General Movement Assessment (GMA) at fidgety age (3-5 months) is a widely used tool for early detection of cerebral palsy. Further to GMA classification, detailed assessment of movement patterns at fidgety age is conducted with the Motor Optimality Score-Revised (MOS-R). Inter-rater reliability and agreement are properties that inform test application and interpretation in clinical and research settings. This study aims to establish the inter-rater reliability and agreement of the GMA classification and MOS-R in a large population-based sample. METHODS: A cross-sectional study of 773 infants from birth-cohort in Perth, Western Australia. GMA was conducted on home-recorded videos collected between 12 + 0 and 16 + 6 weeks post term age. Videos were independently scored by two masked experienced assessors. Inter-rater reliability and agreement were assessed using intraclass correlation coefficient and limits of agreement respectively for continuous variables, and Cohen's Kappa and Gwet's Agreement Coefficient, and percentage agreement respectively for discrete variables. RESULTS: The classification of GMA showed almost perfect reliability (AC1 = 0.999) and agreement (99.9 %). Total MOS-R scores showed good-excellent reliability (ICC 0.857, 95 % CI 0.838-0.876) and clinically acceptable agreement (95 % limits of agreement of ±2.5 points). Substantial to almost perfect reliability and agreement were found for all MOS-R domain subscores. While MOS-R domains with higher redundancy in their categorisation have higher reliability and agreement, inter-rater reliability and agreement are substantial to almost perfect at the item level and are consistent across domains. CONCLUSION: GMA at fidgety age shows clinically acceptable inter-rater reliability and agreement for GMA classification and MOS-R for population-based cohorts assessed by experienced assessors.

Efficacy of Early Intervention for Infants With Cerebral Palsy in an LMIC: An RCT.

OBJECTIVE: To test efficacy of a parent-delivered multidomain early intervention (Learning through Everyday Activities with Parents [LEAP-CP]) for infants with cerebral palsy (CP) compared with equal-dose of health advice (HA), on (1) infant development; and (2) caregiver mental health. It was hypothesized that infants receiving LEAP-CP would have better motor function, and caregivers better mental health. METHODS: This was a multisite single-blind randomized control trial of infants aged 12 to 40 weeks corrected age (CA) at risk for CP (General Movements or Hammersmith Infant Neurologic Examination). Both LEAP-CP and HA groups received 15 fortnightly home-visits by a peer trainer. LEAP-CP is a multidomain active goal-directed intervention. HA is based on Key Family Practices, World Health Organization. Primary outcomes: (1) infants at 18 months CA: Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT mobility); and (2) caregiver: Depression Anxiety and Stress Scale. RESULTS: Of eligible infants, 153 of 165 (92.7%) were recruited (86 males, mean age 7.1±2.7 months CA, Gross Motor Function Classification System at 18 m CA: I = 12, II = 25, III = 9, IV = 18, V = 32). Final data were available for 118 (77.1%). Primary (PEDI-CAT mobility mean difference = 0.8 (95% CI -1.9 to 3.6) P = .54) and secondary outcomes were similar between-groups. Modified-Intention-To-Treat analysis on n = 96 infants with confirmed CP showed Gross Motor Function Classification System I and IIs allocated to LEAP-CP had significantly better scores on PEDI-CAT mobility domain (mean difference 4.0 (95% CI = 1.4 to 6.5), P = .003) compared with HA. CONCLUSIONS: Although there was no overall effect of LEAP-CP compared with dose-matched HA, LEAP-CP lead to superior improvements in motor skills in ambulant children with CP, consistent with what is known about targeted goal-directed training.

Effect of growth hormone deficiency on brain structure, motor function and cognition.

The growth hormone-insulin-like growth factor-1 axis plays a role in normal brain growth but little is known of the effect of growth hormone deficiency on brain structure. Children with isolated growth hormone deficiency (peak growth hormone <6.7 µg/l) and idiopathic short stature (peak growth hormone >10 µg/l) underwent cognitive assessment, diffusion tensor imaging and volumetric magnetic resonance imaging prior to commencing growth hormone treatment. Total brain, corpus callosal, hippocampal, thalamic and basal ganglia volumes were determined using Freesurfer. Fractional anisotropy (a marker of white matter structural integrity) images were aligned and tract-based spatial statistics performed. Fifteen children (mean 8.8 years of age) with isolated growth hormone deficiency [peak growth hormone <6.7 µg/l (mean 3.5 µg/l)] and 14 controls (mean 8.4 years of age) with idiopathic short stature [peak growth hormone >10 µg/l (mean 15 µg/l) and normal growth rate] were recruited. Compared with controls, children with isolated growth hormone deficiency had lower Full-Scale IQ (P < 0.01), Verbal Comprehension Index (P < 0.01), Processing Speed Index (P < 0.05) and Movement-Assessment Battery for Children (P < 0.008) scores. Verbal Comprehension Index scores correlated significantly with insulin-like growth factor-1 (P < 0.03) and insulin-like growth factor binding protein-3 (P < 0.02) standard deviation scores in isolated growth hormone deficiency. The splenium of the corpus callosum, left globus pallidum, thalamus and hippocampus (P < 0.01) were significantly smaller; and corticospinal tract (bilaterally; P < 0.045, P < 0.05) and corpus callosum (P < 0.05) fractional anisotropy were significantly lower in the isolated growth hormone deficiency group. Basal ganglia volumes and bilateral corticospinal tract fractional anisotropy correlated significantly with Movement-Assessment Battery for Children scores, and corpus callosum fractional anisotropy with Full-Scale IQ and Processing Speed Index. In patients with isolated growth hormone deficiency, white matter abnormalities in the corpus callosum and corticospinal tract, and reduced thalamic and globus pallidum volumes relate to deficits in cognitive function and motor performance. Follow-up studies that investigate the course of the structural and cognitive deficits on growth hormone treatment are now required to confirm that growth hormone deficiency impacts significantly on brain structure, cognitive function and motor performance.

Identification of infants with major cognitive delay using parental report.

AIM: The collection of data on longer-term neurodevelopmental outcomes within large neonatal randomized controlled trials by trained assessors can greatly increase costs and present many operational difficulties. The aim of this study was to develop a more practical alternative for identifying major cognitive delay in infants at the age of 24 months, based on parental reports. METHOD: A sample of 476 infants (206 female, 270 male) previously diagnosed with neonatal sepsis (mean birthweight 1329g [SD 865g], mean gestational age at birth 28.7wks [SD 4.5wks]) from the International Neonatal Immunotherapy Study were assessed using the Parent Report of Children's Abilities - Revised and the Bayley Scales of Infant Development, 2nd edition. Logistic regression was used to model the association between the risk of major cognitive delay (i.e. Bayley Scales of Infant Development Mental Development Index <55) and the Parent Report of Children's Abilities - Revised data. RESULTS: The receiver operating characteristic curves for a number of predictive models were constructed - each achieved an area under the curve of at least 90%. The sensitivity, specificity, positive predictive value, and negative predictive value of a number of points on the receiver operating characteristic curves are presented. INTERPRETATION: The Parent Report of Children's Abilities - Revised is a practical tool for identifying major cognitive delay in infants at 24 months.

Characteristics of children with cerebral palsy in the ORACLE children study.

AIMS: We have identified an excess of children with cerebral palsy (CP) born to women who received antibiotic treatment for spontaneous preterm labour (SPL). This nested study investigated the profile of impairment among children with CP in the ORACLE Children Study (OCS), and contrasted outcomes with those in 4Child, a population CP registry. METHOD: The study group comprised 167 children aged from 7 to 10 years (100 males, 67 females) with CP from the OCS, who were subdivided into a preterm rupture of membranes (PROM) group (87 children) and an SPL group (80 children). The OCS sought follow-up information regarding the health and behaviour of surviving children at 7 years of age in the UK using a parent-report postal questionnaire. Families provided further information to define wider aspects of function and were offered a physiotherapy assessment. RESULTS: The prevalence of CP was higher among children in the OCS than among those in 4Child (standardized morbidity ratios: SPL group, 3.12 [95% confidence interval {CI} 2.47-3.87); PROM group: 1.56 (CI 1.24-1.92)]. The proportion of children with CP born after 32 weeks of gestation was higher in in the SPL group (73%) than in the PROM group (30%); the prevalence of CP was higher in the SPL group than in the PROM group or 4Child. Children with CP in the OCS tended to have similar distributions of neuroimpairment as children in 4Child, but motor impairment and associated vision and hearing problems were found to be less severe. INTERPRETATION: The pattern of CP in both the PROM and the SPL groups was similar, but functional outcomes were milder, compared with children with CP in the general population. However, in these groups the risk of CP was increased independently of gestational age. This is consistent with findings that ongoing inflammatory damage can cause CP.

From guidelines to practice: A retrospective clinical cohort study investigating implementation of the early detection guidelines for cerebral palsy in a state-wide early intervention service.

OBJECTIVES: To report on knowledge translation strategies and outcomes from the implementation of the early detection guidelines for cerebral palsy (CP) in a state-wide tertiary early intervention (EI) service and investigate the impact of social determinants on clinical services. DESIGN: Retrospective longitudinal cohort study. SETTING: The Western Australia tertiary paediatric EI service. PARTICIPANTS: EI clinicians, consumers and children using the EI service. OUTCOME MEASURES: Knowledge translation strategies including consumer perspectives, clinician training and Communities of Practice (CoP) guided implementation. We measured changes in referral number and age, delivery of early detection and intervention following the implementation of the guidelines. Exposure to adverse childhood experiences (ACEs), appointment non-attendance (DNA) rates, remoteness and socioeconomic quintiles were used to measure social determinants of health using negative binomial (Incidence Rate Ratios, IRR) and logistic regression (Odds Ratios, ORs). RESULTS: Ten consumers participated in Focus Groups, 100 clinicians were trained and 22 clinicians established a monthly CoP. Referrals increased fourfold to 511 children. Corrected gestational age at referral decreased from a median of 16.1 to 5.1 months (p<0.001) and at first appointment from 18.8 to 6.8 months (p<0.001). Children living in social disadvantage had the highest DNA risk (quintile 1 vs 5: IRR 2.2, 95% CI 1.1 to 4.6, p=0.037). Children exposed to ACEs had higher odds of living in social disadvantage (quintile 1 vs 5, OR=3.8, 95% CI 1.4 to 10.0, p=0.007). No significant association was found between remoteness and DNA rate or ACE score. CONCLUSIONS: Implementation strategies reduced referral age and improved the delivery of early detection assessments. Further investigation of the association between social disadvantage, DNA risk and ACE score is required in the development of a state-wide early detection network.

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways.

Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A-->G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with "low-penetrant" mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.

Developing a schedule to identify social communication difficulties and autism spectrum disorder in young children with visual impairment.

Available observational tools used in the identification of social communication difficulties and diagnosis of autism spectrum disorder (ASD) rely partly on visual behaviours and therefore may not be valid in children with visual impairment. A pilot observational instrument, the Visual Impairment and Social Communication Schedule (VISS), was developed to aid in identifying social communication difficulties and ASD in young children with visual impairment affected by congenital disorders of the peripheral visual system (disorders of the globe, retina, and anterior optic nerve). The VISS was administered to 23 consecutive children (age range 1 y 9 mo-6 y 11 mo, mean 4 y 1 mo [SD 1.6]; 12 males, 11 females) with visual impairment (nine with severe and 14 with profound visual impairment). Item analysis was carried out by fit of the items to the Rasch model. Validity of the VISS was explored by comparison with the Childhood Autism Rating Scale (CARS) score, and the clinical ASD diagnosis (n=9). Correlation between the VISS and CARS total scores was highly significant (Spearman's rho=-0.89; p=0.01). Below threshold rating on the VISS (score of 35) showed good agreement with the clinical ASD diagnosis (sensitivity 89%, specificity 100%). This preliminary study shows the VISS to be a promising schedule to aid the identification of ASD in young children with visual impairment.

Early Moves: a protocol for a population-based prospective cohort study to establish general movements as an early biomarker of cognitive impairment in infants.

INTRODUCTION: The current diagnostic pathways for cognitive impairment rarely identify babies at risk before 2 years of age. Very early detection and timely targeted intervention has potential to improve outcomes for these children and support them to reach their full life potential. Early Moves aims to identify early biomarkers, including general movements (GMs), for babies at risk of cognitive impairment, allowing early intervention within critical developmental windows to enable these children to have the best possible start to life. METHOD AND ANALYSIS: Early Moves is a double-masked prospective cohort study that will recruit 3000 term and preterm babies from a secondary care setting. Early Moves will determine the diagnostic value of abnormal GMs (at writhing and fidgety age) for mild, moderate and severe cognitive delay at 2 years measured by the Bayley-4. Parents will use the Baby Moves smartphone application to video their babies' GMs. Trained GMs assessors will be masked to any risk factors and assessors of the primary outcome will be masked to the GMs result. Automated scoring of GMs will be developed through applying machine-based learning to the data and the predictive value for an abnormal GM will be investigated. Screening algorithms for identification of children at risk of cognitive impairment, using the GM assessment (GMA), and routinely collected social and environmental profile data will be developed to allow more accurate prediction of cognitive outcome at 2 years. A cost evaluation for GMA implementation in preparation for national implementation will be undertaken including exploring the relationship between cognitive status and healthcare utilisation, medical costs, health-related quality of life and caregiver burden. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Medical Research Ethics Committee of Joondalup Health Services and the Health Service Human Research Ethics Committee (1902) of Curtin University (HRE2019-0739). TRIAL REGISTRATION NUMBER: ACTRN12619001422112.

Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study.

BACKGROUND: The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known. METHODS AND FINDINGS: Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%). CONCLUSION: The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.

Use of genome-wide SNP homozygosity mapping in small pedigrees to identify new mutations in VSX2 causing recessive microphthalmia and a semidominant inner retinal dystrophy.

Mutations in the visual system homeobox 2 gene (VSX2, also known as CHX10), which encodes a retinal transcription factor from the paired homeobox family, have been implicated in recessive isolated microphthalmia. In this study, we use genome-wide single nucleotide polymorphism homozygosity mapping in unrelated small consanguineous pedigrees and a candidate gene approach to identify three further causative VSX2 mutations (two novel and one previously reported). All affected individuals with homozygous mutations had bilateral anophthalmia or severe microphthalmia with absent vision. In addition, we identified a novel inner retinal dystrophy in two carrier parents suggesting a semidominant effect for this particular VSX2 mutation. A further study of individuals with retinal degenerative conditions may reveal a causative role for heterozygous mutations in VSX2.

Social communication difficulties and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia.

AIM: the aim of this study was to study systematically social, communication, and repetitive/restrictive (SCRR) behavioural difficulties and clinical autism spectrum disorder (ASD) in children with optic nerve hypoplasia (ONH) and/or septo-optic dysplasia (SOD), and to investigate the relationship between visual impairment, SCRR difficulties, ASD, and cognition. METHOD: a case-note study of clinic records from a specialist developmental vision service was completed. Standardized assessments of vision and development and clinician judgements about SCRR difficulties and clinical ASD were made by a multidisciplinary team. RESULTS: a total of 45 females and 38 males (mean age 3y 5mo; range 10mo-6y 10mo) with ONH or SOD and profound visual impairment (PVI) or severe visual impairment (SVI) were assessed. A total of 58% of children had at least one SCRR difficulty, and 31% had a clinical diagnosis of ASD. The prevalence of ASD was slightly higher in children with SOD than in children with ONH (36% vs 26%) also slightly more frequent in children with PVI than in children with SVI (36% vs 27%). The prevalence of SCRR difficulties was statistically higher in children with PVI than in children with SVI (p=0.003). Clinical ASD was most likely to be diagnosed between 2 years 4 months and 4 years 6 months. Development was significantly delayed in children with ASD compared with children without social communication difficulties (p=0.001). INTERPRETATION: children with SVI or PVI are at risk of SCRR difficulties and clinical ASD. Children with ONH and/or SOD and visual impairment have a similar risk of developing clinical ASD as other visual impairment groups. However, ASD prevalence data from this study are a minimum estimate, as some young children may have developed ASD behaviours in later childhood. Developmental surveillance for children with ONH and/or SOD should continue until at least the age of 4 years 6 months.