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2.  Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy 
In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years.
Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy.
Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years.
Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability.
PMCID: PMC4324462  PMID: 24957482
3.  Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized trial 
Developmental medicine and child neurology  2013;56(1):10.1111/dmcn.12243.
The aim of this study was to determine the feasibility and efficacy of five treatments of 6Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) combined with constraint-induced movement therapy (CIMT) to promote recovery of the paretic hand in children with congenital hemiparesis.
Nineteen children with congenital hemiparesis aged between 8 and 17 years (10 males, nine females; mean age 10y 10mo, SD 2y 10mo; Manual Ability Classification Scale levels I-III) underwent five sessions of either real rTMS (n=10) or sham rTMS (n=9) alternated daily with CIMT. CIMT consisted of 13 days of continuous long-arm casting with five skin-check sessions. Each child received a total of 10 hours of one-to-one therapy. The primary outcome measure was the Assisting Hand Assessment (AHA) and the secondary outcome variables were the Canadian Occupational Performance Measure (COPM) and stereognosis. A Wilcoxon signed-rank sum test was used to analyze differences between pre- and post-test scores within the groups. Analysis of covariance was used to compute mean differences between groups adjusting for baseline. Fisher’s exact test was used to compare individual change in AHA raw scores with the smallest detectable difference (SDD) of 4 points.
All participants receiving treatment finished the study. Improvement in AHA differed significantly between groups (p=0.007). No significant differences in the secondary outcome measures were found. Eight out of 10 participants in the rTMS/CIMT group showed improvement greater than the SDD, but only two out of nine in the sham rTMS/CIMT group showed such improvement (p=0.023). No serious adverse events occurred.
Primed, low-frequency rTMS combined with CIMT appears to be safe, feasible, and efficacious in pediatric hemiparesis. Larger clinical trials are now indicated.
PMCID: PMC3864983  PMID: 23962321
4.  Psychometrics of the neonatal oral motor assessment scale 
Developmental medicine and child neurology  2013;55(12):10.1111/dmcn.12202.
To establish the psychometrics of the Neonatal Oral Motor Assessment Scale (NOMAS).
In this prospective cohort study of 75 preterm infants (39 females,36 males) born at 30 weeks' or less gestation (mean gestational age 26.56wk, SD 1.90, range 23–30wk; mean birthweight 967.33g, SD 288.54, range 480–2240), oral feeding was videotaped before discharge from the neonatal intensive care unit (NICU) discharge. The NOMAS was used to classify feeding as normal, disorganized, or dysfunctional. Neurobehavior was assessed at term equivalent, and infants underwent magnetic resonance imaging. Children returned for developmental testing at 2 years corrected age. Associations between NOMAS scores and (1) neurobehavior, (2) cerebral injury and metrics, and (3) developmental outcome were investigated using χ2-analyses, t-tests, and linear regression. For reliability, six certified NOMAS evaluators rated five randomly selected NOMAS recordings and re-scored them in a second randomized order. Reliability was calculated with Cohen’s kappa coefficient.
Dysfunctional NOMAS scores were associated with lower Dubowitz scores [t=–2.14; mean difference –2.32 (95% confidence interval [CI] –0.157 to –4.49); p=0.036], higher stress on the NICU Network Neurobehavioral Scale (t=2.61; mean difference 0.073 [95% CI 0.017 to 0.129]; p=0.0110, and decreased transcerebellar diameter (t=–2.22; mean difference –2.04 [CI=–3.89 to –0.203]; p=0.03). No significant associations were found between NOMAS scores and 2 year outcome.
Some concurrent validity was established with associations between NOMAS scores and measures of infant behavior and cerebral structure. The NOMAS did not show predictive validity in this study of preterm infants at high risk of developmental delay. Reliability was variable and suboptimal.
PMCID: PMC3830735  PMID: 23869958
5.  Genetic disorders of thyroid metabolism and brain development 
Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain-thyroid’ disorders.
PMCID: PMC4231219  PMID: 24665922
6.  Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum 
Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C β1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1. A case note review and molecular genetic investigations were performed for a child, approximately 10 months of age, admitted to Johns Hopkins University Hospital for developmental delay and new-onset seizures. The patient presented at 6 months of age with developmental delay, followed by the onset of intractable, focal, and generalized seizures associated with developmental regression from 10 months of age. Presently, at 2 years of age, the child has severe motor and cognitive delays. Diagnostic microarray revealed a heterozygous 476kb deletion of 20p12.3 (encompassing PLCB1), which was also detected in the mother. The genomic breakpoints for the heterozygous deletion were determined. In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father. Advances in molecular genetic testing have greatly improved diagnostic rates in EIEE, and this report further confirms the important role of microarray investigation in this group of disorders. PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes.
PMCID: PMC4230412  PMID: 24684524
7.  Early intervention after perinatal stroke: Opportunities and challenges 
Perinatal stroke is the commonest cause of hemiplegic cerebral palsy. No standardised early intervention exists despite evidence for a critical time window for activity-dependent plasticity to mould corticospinal tract development in the first few years of life. Intervention during this unique period of plasticity could mitigate the consequences of perinatal stroke to an extent not possible with later intervention, by preserving the normal pattern of development of descending motor pathways. This article outlines the broad range of approaches currently under investigation. Improved early detection and outcome prediction remain important goals, despite significant progress in this area.
PMCID: PMC4020312  PMID: 24528276
8.  Cerebral palsy and aging 
Cerebral palsy (CP), the most common major disabling motor disorder of childhood, is frequently thought of as a condition that affects only children. Deaths in children with CP, never common, have in recent years become very rare, unless the child is very severely and multiply disabled. Thus, virtually all children assigned the diagnosis of CP will survive into adulthood. Attention to the adult with CP has been sparse, and the evolution of the motor disorder as the individual moves through adolescence, young adulthood, middle age, and old age is not well understood. Nor do we know what happens to other functional domains, such as communication and eating behavior, in adults with CP. Although the brain injury that initially causes CP by definition does not progressively worsen through the lifetime, the effects of CP manifest differently throughout the life span. The aging process must inevitably interact with the motor disorder, but we lack systematic, large-scale follow-up studies of children with CP into adulthood and through adulthood with thorough assessments performed over time.
In this paper we summarize what is known of the epidemiology of CP throughout the life span, beginning with mortality and life expectancy, then survey what is known of functioning, ability, and quality of life of adults with CP. We conclude by describing a framework for future research on CP and aging that is built around the World Health Organization's International Classification of Functioning, Disability, and Health (ICF) and suggest specific tools and approaches for conducting that research in a sound manner.
PMCID: PMC4183123  PMID: 19740206
9.  Neuropsychological function in children with primary complex motor stereotypies 
Complex motor stereotypies (CMS) are patterned, repetitive, rhythmic, and involuntary movements that persist over time. They are divided into two subgroups dependent on the presence of other developmental problems: ‘primary’ (development is otherwise typical) or ‘secondary’ (associated with autism, intellectual disability, or sensory deficits). There are no currently published studies that examine neuropsychological function in children with primary CMS. This case–control study examines whether children with primary CMS manifest neurobehavioral deficits.
Fifty-seven children with primary CMS (32 males, 25 females; mean age 6y 8mo, SD 2y 4mo, range 4–12y) with negative screens for autism and 57 comparison participants (32 males, 25 females; mean age 6y 6mo, SD 2y 1mo) completed neuropsychological assessments of IQ, reading ability, attention, language, and motor and executive functions. Parents completed ratings of their child’s repetitive movement severity.
The CMS group performed significantly less well than comparison participants on motor skills and IQ tests (both p<0.01), although IQ was consistently in the average range. One-third of the CMS group showed signs of developmental motor coordination difficulties. Parent report of stereotypy severity was significantly associated with parent report of inattention and executive dysfunction.
Children with primary CMS were found to have largely intact neuropsychological profiles. Stereotypy severity appears to be associated with executive dysfunction. Although motor difficulties were observed in children with CMS, these were not correlated with parent report of symptom severity.
PMCID: PMC4162830  PMID: 24814517
10.  Cortical speech sound differentiation in the neonatal intensive care unit predicts cognitive and language development in the first 2 years of life 
Neurodevelopmental delay in childhood is common in infants born preterm, but is difficult to predict before infants leave the neonatal intensive care unit (NICU). We hypothesized that event-related potential (ERP) methodology characterizing the cortical differentiation of speech sounds in hospitalized infants would predict cognitive and language outcomes during early childhood.
We conducted a prospective study of 57 infants in NICU (60% male, gestational age at birth 24–40wks), quantifying the amplitude of ERP responses to speech sounds before discharge (median gestational age 37.1wk), followed by standardized neurodevelopmental assessments at 12 months and 24 months. Analyses were performed using ordinary least squares linear regression.
Overall validity of constructs using all ERP variables, as well as sex, maternal education, gestational age, and age at ERP, was good and allowed significant prediction of cognitive and communication outcomes at 12 and 24 months (R2=22–42%; p<0.05). Quantitative models incorporating specific ERPs, gestational age, and age at ERP explained a large proportion of the variance in cognition and receptive language on the Bayley Scales of Infant Development at 24 months (R2>50%; p<0.05).
This study establishes ERP methodology as a valuable research tool to quantitatively assess cortical function in the NICU and to predict meaningful outcomes in early childhood.
PMCID: PMC3740084  PMID: 23799953
11.  Classification of intellectual disability using the Wechsler Intelligence Scale for Children: Full Scale IQ or General Abilities Index? 
We examined the implications of using the Full Scale Intelligence Quotient (FSIQ) versus the General Abilities Index (GAI) for determination of intellectual disability using the Wechsler Intelligence Scales for Children, fourth edition (WISC-IV).
Children referred for neuropsychological assessment (543 males, 290 females; mean age 10y 5mo, SD 2y 9mo, range 6–16y) were administered the WISC-IV and the Adaptive Behavior Assessment System, Second Edition (ABAS-II).
GAI and FSIQ were highly correlated; however, fewer children were identified as having intellectual disability using GAI (n=159) than when using FSIQ (n=196). Although the 44 children classified as having intellectual disability based upon FSIQ (but not GAI) had significantly higher adaptive functioning scores than those meeting intellectual disability criteria based upon both FSIQ and GAI, mean adaptive scores still fell within the impaired range. FSIQ and GAI were comparable in predicting impairments in adaptive functioning.
Using GAI rather than FSIQ in intellectual disability diagnostic decision making resulted in fewer individuals being diagnosed with intellectual disability; however, the mean GAI of the disqualified individuals was at the upper end of criteria for intellectual impairment (standard score 75), and these individuals remained adaptively impaired. As GAI and FSIQ were similarly predictive of overall adaptive functioning, the use of GAI for intellectual disability diagnostic decision making may be of limited value.
PMCID: PMC3748610  PMID: 23859669
12.  Stability of motor function and associated impairments between childhood and adolescence in young people with cerebral palsy in Europe 
The aim of the study was to investigate whether impairments associated with cerebral palsy were stable between childhood and adolescence.
The Study of Participation of Children with Cerebral Palsy Living in Europe (SPARCLE) longitudinal study was conducted in nine European regions. In total, 818 children aged 8 to 12 years were randomly selected from population-based registers; 594 (73%) were followed up at the age of 13 to 17 years (344 males, 250 females; median age 10y 4mo) Research associates visited them in their homes and recorded their motor function and additional impairments. Stability of impairment was assessed using the weighted kappa coefficient.
The proportion of participants whose level of impairment remained unchanged varied from 63% for fine motor function to 98% for hearing. For gross motor function, communication, and cognitive level, the kappa and the lower bound of its 95% confidence interval (CI) were above 0.75, indicating stability between childhood and adolescence; for fine motor function and feeding, the kappa was above 0.75 but the lower bound of the 95% CI was below 0.75, indicating probable stability; for seizures and vision, the kappa was below 0.75, although the upper bound of the 95% CI was above 0.75, indicating possible change; for hearing the kappa and its entire CI were below 0.75, indicating change. Overall, 81% of participants had no seizures in childhood, of whom 93% were seizure-free in adolescence.
Motor function and additional impairments were generally stable between childhood and adolescence.
PMCID: PMC4132119  PMID: 24641712
13.  Level of purposeful hand function as a marker of clinical severity in Rett syndrome 
We investigated relationships between hand function and genotype and aspects of phenotype in Rett syndrome.
Video assessment in naturalistic settings was supplemented by parent-reported data in a cross-sectional study of 144 females with a mean age of 14 years 10 months (SD 7y 10mo; range 2y to–31y 10mo), 110 of whom had a mutation of the methyl CpG binding protein 2 (MECP2) gene. Ordinal logistic regression was used to assess relationships between hand function and MECP2 mutation, age, a modified Kerr score, Functional Independence Measure for children (WeeFIM), ambulation level, and frequency of hand stereotypies.
Approximately two-thirds of participants demonstrated purposeful hand function, ranging from simple grasping skills to picking up and manipulating small objects. In participants with a confirmed MECP2 mutation, those with the p.R168X mutation had the poorest hand function on multivariate analysis with C-terminal deletion as the baseline (odds ratio [OR] 0.19; 95% confidence interval [CI] 0.04–0.95), whereas those with the p.R133C or p.R294X mutation had better hand function. Participants aged 19 years or older had lower hand function than those aged less than 8 years (OR 0.36; 95% CI 0.14–0.92). Factors that were associated with better hand function were lower Kerr scores for a 1-point increase in score (OR 0.77; 95% CI 0.69–0.86), higher WeeFIM scores for a 1-point increase in score (OR 1.08; 95% CI 1.04–1.12), and greater ambulation than those completely dependent on carers for mobility (OR 22.64; 95% CI 7.02–73.08). The results for participants with a confirmed pathogenic mutation were similar to results obtained when participants without a mutation were also included.
Our novel assessment of hand function in Rett syndrome correlated well with known profiles of common MECP2 mutations and overall clinical severity. This promising assessment could measure clinical responses to therapy.
PMCID: PMC4122219  PMID: 20345957
14.  Adaptive behavior and later school achievement in children with early-onset epilepsy 
To determine whether early measures of adaptive behavior are predictive of later school difficulties and achievement in otherwise neurotypical (unimpaired) children with onset of epilepsy during the pre-school years.
In a prospective cohort study, parents completed the Vineland Adaptive Behavior Scales (VABS) for children who were aged 5 years or less at epilepsy diagnosis. Eight to nine years later, the children were assessed using the Wechsler Intelligence Scales for Children (WISC), the Wide Range Achievement Test (WRAT), and the Child Behavior Checklist (CBCL). Associations of VABS scores with later WRAT and CBCL scores were tested.
A total of 108 neurotypical children (64 males, 44 females; mean age at testing 11y 11mo, SD 2y) were studied. After adjustment for IQ and other factors, there was an increase of 0.15 points (95% confidence interval [CI] 0.03–0.27 points; p=0.03) and 0.14 points (95% CI 0.0–0.28 points; p=0.05) in WRAT reading and spelling scores for each 1-point increment in the VABS communication score. Corresponding numbers for the VABS socialization score were 0.20 (95% CI 0.08–0.32; p=0. 005) and 0.17 (95% CI 0.05–0.29; p=0.005).
In neurotypical preschool children with epilepsy, early social and communication scores predict later school performance. These findings raise questions about opportunities for early identification and intervention for children at greatest risk.
PMCID: PMC3676436  PMID: 23534842
15.  Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach 
As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy.
The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype.
A total of 180 SRS questionnaires were filled out in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21y, range 4–63y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9y range 4–22y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism.
Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific for these conditions.
PMCID: PMC4071146  PMID: 23205844
16.  Reduced satellite cell population may lead to contractures in children with cerebral palsy 
Satellite cells are the stem cells residing in muscle responsible for skeletal muscle growth and repair. Skeletal muscle in cerebral palsy (CP) has impaired longitudinal growth that results in muscle contractures. We hypothesized that the satellite cell population would be reduced in contractured muscle.
We compared the satellite cell populations in hamstring muscles from participants with CP contracture (n=8; six males, two females; age range 6–15y; Gross Motor Function Classification System [GMFCS] levels II–V; 4 with hemiplegia, 4 with diplegia) and from typically developing participants (n=8; six males, two females, age range 15–18y). Muscle biopsies were extracted from the gracilis and semitendinosus muscles and mononuclear cells were isolated. Cell surface markers were stained with fluorescently conjugated antibodies to label satellite cells (neural cell adhesion molecule) and inflammatory and endothelial cells (CD34 and CD4 respectively). Cells were analyzed using flow cytometry to determine cell populations.
After gating for intact cells a mean of 12.8% (SD 2.8%) were determined to be satellite cells in typically developing children, but only 5.3% (SD 2.3%;p<0.05) in children with CP. Hematopoietic and endothelial cell types were equivalent in typically developing children and children with CP (p>0.05) suggesting the isolation procedure was valid.
A reduced satellite cell population may account for the decreased longitudinal growth of muscles in CP that develop into fixed contractures or the decreased ability to strengthen muscle in CP. This suggests a unique musculoskeletal disease mechanism and provides a potential therapeutic target for debilitating muscle contractures.
PMCID: PMC4054943  PMID: 23210987
17.  Epilepsy drives autism in neurodevelopmental disorders 
PMCID: PMC4051495  PMID: 23320573
18.  Neonatal white matter abnormality predicts childhood motor impairment in very preterm children 
Children born very preterm are at risk for impaired motor performance ranging from cerebral palsy (CP) to milder abnormalities, such as developmental coordination disorder. White matter abnormalities (WMA) at term have been associated with CP in very preterm children; however, little is known about the impact of WMA on the range of motor impairments. The aim of this study was to assess whether WMA were predictive of all levels of motor impairments in very preterm children.
Two hundred and twenty-seven very preterm infants (<30wks’ gestational age or birthweight <1250g) had brain magnetic resonance imaging at term-equivalent age to assess for WMA, which were categorized as nil, mild, or moderate to severe. At 5 years of age children were classified as having a moderate to severe motor impairment if they were below the 5th centile or mild to severe motor impairment if their score placed them no higher than the 15th centile on the Movement Assessment Battery for Children (MABC). WMA (nil vs mild and nil vs moderate–severe) were explored as predictors of motor impairment using logistic regression. Analyses were repeated adjusting for the effects of other perinatal variables and excluding children with CP.
Of the 193 very preterm children (97 males, 96 females) assessed with the MABC, 53 (27%) were classified as having a moderate to severe motor impairment and 96 (50%) a mild to severe motor impairment. WMA were predictive of motor impairment in very preterm children, with mild versus no WMA increasing the odds of moderate to severe motor impairment by over fivefold (odds ratio [OR] 5.6; 95% confidence interval [CI] 1.9–16.1; p=0.002) and mild to severe impairment by twofold (OR 2.2; 95% CI 1.1–4.2; p=0.02). Compared with no WMA, moderate to severe WMA increased the odds for moderate to severe impairment 19-fold (OR 19.4; 95% CI 5.6–66.7; p<0.001) and for mild to severe motor impairment ninefold (OR 9.4; 95% CI 3.2–28.1; p<0.001). Results remained similar after controlling for several potential confounders and after excluding 14 children who had CP at age 2 years.
WMA predict motor impairment at 5 years, with rates of impairment increasing with more severe WMA. Very preterm children with any WMA at term require follow-up throughout childhood.
PMCID: PMC4040368  PMID: 22014319
19.  Iron-deficiency anemia in infancy and poorer cognitive inhibitory control at age 10 years 
The aim of this study was to assess the effects of iron-deficiency anemia (IDA) in infancy on executive functioning at age 10 years, specifically inhibitory control on the Go/No-Go task. We predicted that children who had IDA in infancy would show poorer inhibitory control.
We assessed cognitive inhibitory control in 132 Chilean children (mean [SD] age 10y 0mo [1mo]): 69 children had IDA in infancy (45 males, 24 females) and 63 comparison children who did not have IDA (26 males, 37 females). Participants performed the Go/No-Go task with event-related potentials. Group differences in behavioral (accuracy, reaction time) and electrophysiological outcomes (N2 and P300 components) were analyzed using repeated-measures analyses of variance. N2 and P300 are interpreted to reflect attention and resource allocation respectively.
Relative to comparison participants, children who had IDA in infancy showed slower reaction time (mean [SE], 528.7ms [14.2] vs 485.0ms [15.0], 95% confidence interval [CI] for difference between groups 0.9–86.5); lower accuracy (95.4% [0.5] vs 96.9% [0.6], 95% CI −3.0 to −0.1); longer latency to N2 peak (378.9ms [4.9] vs 356.9ms [5.0], 95% CI 7.5–36.6); and smaller P300 amplitude (4.5μV [0.8] vs 7.6μV [0.9], 95% CI–5.5 to −0.5).
IDA in infancy was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy. These findings are consistent with the long-lasting effects of early IDA on myelination and/or prefrontal–striatal circuits where dopamine is the major neurotransmitter.
PMCID: PMC3625473  PMID: 23464736
20.  The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders 
A group of disorders with disparate symptomatology, including congenital cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease, and polydactyly, have recently been united under a single disease mechanism called ‘ciliopathies’. The ciliopathies are due to defects of the cellular antenna known as the primary cilium, a microtubule-based extension of cellular membranes found in nearly all cell types. Key among these ciliopathies is Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation* with a pathognomonic ‘molar tooth sign’ on brain magnetic resonance imaging. The importance of ciliary function in neuronal development has been appreciated only in the last decade with the classification of Joubert syndrome as a ciliopathy. This, together with the identification of many of the clinical features of ciliopathies in individuals with Joubert syndrome and the localization of Joubert syndrome’s causative gene products at or near the primary cilium, have defined a new class of neurological disease. Cilia are involved in diverse cellular processes including protein trafficking, photoreception, embryonic axis patterning, and cell cycle regulation. Ciliary dysfunction can affect a single tissue or manifest as multi-organ involvement. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders.
PMCID: PMC3984879  PMID: 21679365
21.  Apolipoprotein E polymorphisms and severity of cerebral palsy: a cross-sectional study in 255 children in Norway 
The aim of this study was to examine whether the presence of the apolipoprotein E (ApoE) allele APOEε4 is associated with less severe manifestations of cerebral palsy (CP), consistent with the suggested beneficial effect of this allele on neurodevelopment in children.
ApoE genotyping was performed on buccal epithelial cells from 255 children (141 males 114 females; mean age 12y, SD 2y 3mo, range 9–17y) recorded in the Cerebral Palsy Register of Norway. The main outcome measure of CP severity was the Gross Motor Function Classification System (GMFCS). Secondary outcome measures were fine motor function, epilepsy, and the need for gastrostomy tube feeding (GTF).
There was no association between the APOEε4 genotype and GMFCS levels (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.66–1.99). However, the APOEε4 genotype was more often present among children with epilepsy (OR 2.2; 95% CI 1.1–4.2) and/or receiving GTF (OR 2.7; 95% CI 1.1–6.6). Among children with unilateral CP, the presence of APOEε4 was associated with more severe fine motor impairment (OR 2.6; 95% CI 1.3–6.9).
Our main hypothesis that APOEε4 would have a protective effect on neurodevelopment was not supported. Instead, subgroup analyses suggested an adverse effect of the APOEε4 genotype on the developing brain after injury.
PMCID: PMC3600054  PMID: 23384326
22.  Is lower IQ in children with epilepsy due to lower parental IQ? A controlled comparison study 
The aim of this study was to determine the relationship between parent and child full-scale IQ (FSIQ) in children with epilepsy and in typically developing comparison children and to examine parent–child IQ differences by epilepsy characteristics.
The study participants were 97 children (50 males, 47 females; age range 8–18y; mean age 12y 3mo, SD 3y.1mo) with recent-onset epilepsy including idiopathic generalized (n=43) and idiopathic localization-related epilepsies (n=54); 69 healthy comparison children (38 females, 31 males; age range 8–18y; mean age 12y 8mo, SD 3y 2mo), and one biological parent per child. All participants were administered the Wechsler Abbreviated Intelligence Scale. FSIQ was compared in children with epilepsy and typically developing children; FSIQ was compared in the parents of typically developing children and the parents of participants with epilepsy; parent–child FSIQ differences were compared between the groups.
FSIQ was lower in children with epilepsy than in comparison children (p<0.001). FSIQ of parents of children with epilepsy did not differ from the FSIQ of the parents of typically developing children. Children with epilepsy had significantly lower FSIQ than their parents (p<0.001), whereas comparison children did not. The parent–child IQ difference was significantly higher in the group with epilepsy than the comparison group (p=0.043). Epilepsy characteristics were not related to parent–child IQ difference.
Parent–child IQ difference appears to be a marker of epilepsy impact independent of familial IQ, epilepsy syndrome, and clinical seizure features. This marker is evident early in the course of idiopathic epilepsies and can be tracked over time.
PMCID: PMC3570624  PMID: 23216381
23.  Postural asymmetries in young adults with cerebral palsy 
Aim The purpose was to describe posture, ability to change position, and association between posture and contractures, hip dislocation, scoliosis, and pain in young adults with cerebral palsy (CP).
Methods Cross-sectional data of 102 people (63 males, 39 females; age range 19–23y, median 21y) out of a total population with CP was analysed in relation to Gross Motor Function Classification System (GMFCS) levels I (n=38), II (n=21), III (n=13), IV (n=10), and V (n=20). The CP subtypes were unilateral spastic (n=26), bilateral spastic (n=45), ataxic (n=12), and dyskinetic CP (n=19). The Postural Ability Scale was used to assess posture. The relationship between posture and joint range of motion, hip dislocation, scoliosis, and pain was analysed using logistic regression and Spearman’s correlation.
Results At GMFCS levels I to II, head and trunk asymmetries were most common; at GMFCS levels III to V postural asymmetries varied with position. The odds ratios (OR) for severe postural asymmetries were significantly higher for those with scoliosis (OR=33 sitting), limited hip extension (OR=39 supine), or limited knee extension (OR=37 standing). Postural asymmetries correlated to hip dislocations: supine (rs=0.48), sitting (rs=0.40), standing (rs=0.41), and inability to change position: supine (rs=0.60), sitting (rs=0.73), and standing (rs=0.64).
Conclusions Postural asymmetries were associated with scoliosis, hip dislocations, hip and knee contractures, and inability to change position.
This article is commented on by Novak on page 974 of this issue.
PMCID: PMC3906840  PMID: 23834239
24.  The effect of pediatric traumatic brain injury on behavioral outcomes: a systematic review 
To review systematically the empirical evidence on traumatic brain injury (TBI) during childhood and subsequent behavioral problems.
An initial literature search with keywords ‘brain injury,’ ‘children,’ and ‘behavior’ was conducted using Web of Knowledge and PubMed databases. Ancestry was also used. Original research studies published between 1990 and February 2012 focusing on behavioral outcomes of children sustaining TBI from ages 0 to 18 years were included.
Fifty studies, varying considerably in methodologies, were included in the review. Findings showed that up to 50% of brain-injured children are at risk for presenting with behavioral problems and disorders, which may emerge shortly or several years after injury and, importantly, often persist and even worsen with time. These behavioral impairments appear to be moderated by the family environment.
Survivors of childhood TBI are at risk for developing and sustaining behavioral impairments. Stronger research is needed to identify cognitive and environmental factors that contribute to the onset and maintenance of these problems. Healthcare providers should ensure adequate follow-up and assessment of a child’s behavioral, social, and neurocognitive domains. Caregivers should be encouraged to provide positive environments and parenting styles, which may help reduce chronic behavioral problems after brain injury.
PMCID: PMC3593091  PMID: 22998525
25.  Global perspective on early diagnosis and intervention for children with developmental delays and disabilities 
Developmental medicine and child neurology  2012;54(12):10.1111/j.1469-8749.2012.04348.x.
Low- and middle-income countries are experiencing a significant reduction in mortality of children under 5 years of age. This reduction is bringing in its wake large numbers of surviving children with developmental delays and disabilities. Very little attention has been paid to these children, most of whom receive minimal or no support. Thus, there is an urgent need to recognize that improving the quality of life of the survivors must complement mortality reduction in healthcare practice and programs. The incorporation of early evaluation and intervention programs into routine pediatric care is likely to have the most impact on the quality of life of these children. We therefore call for leadership from practitioners, governments, and international organizations to prioritize regular childhood developmental surveillance for possible delays and disabilities, and to pursue early referral for intervention.
PMCID: PMC3840420  PMID: 22803576

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