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Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment. Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85–99, 70–84, 1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ. Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.

The goal of this work was to examine the change in health-related quality of life (HRQOL) and cognitive functioning from early childhood to adolescence in pediatric liver transplantation (LT) recipients. Patients were recruited from 8 North American centers through the Studies of Pediatric Liver Transplantation consortium. A total of 79 participants, ages 11-18 years, previously tested at age 5-6 years in the Functional Outcomes Group study were identified as surviving most recent LT by 2 years and in stable medical follow-up. The Pediatric Quality of Life 4.0 Generic Core Scale, Pediatric Quality of Life Cognitive Function Scale, and PROMIS Pediatric Cognitive Function tool were distributed to families electronically. Data were analyzed using repeated measures and paired t tests. Predictive variables were analyzed using univariate regression analysis. Of the 69 families contacted, 65 (94.2%) parents and 61 (88.4%) children completed surveys. Median age of participants was 16.1 years (range, 12.9-18.0 years), 55.4% were female, 33.8% were nonwhite, and 84.0% of primary caregivers had received at least some college education. Median age at LT was 1.1 years (range, 0.1-4.8 years). The majority of participants (86.2%) were not hospitalized in the last year. According to parents, adolescents had worse HRQOL and cognitive functioning compared with healthy children in all domains. Adolescents reported HRQOL similar to healthy children in all domains except psychosocial, school, and cognitive functioning (P = 0.02; P 0.001; P = 0.04). Participants showed no improvement in HRQOL or cognitive functioning over time. For cognitive and school functioning, 60.0% and 50.8% of parents reported "poor" functioning, respectively (1 standard deviation below the healthy mean). Deficits in HRQOL seem to persist in adolescence. Over half of adolescent LT recipients appear to be at risk for poor school and cognitive functioning, likely reflecting attention and executive function deficits.

OBJECTIVES The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment. METHODS Participants (ages 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3-5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6-12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (mean = 100 ± 15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression. RESULTS Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104 ± 14, P

Objectives Despite the need for monitoring cognition for minimal hepatic encephalopathy (MHE) in children with portal hypertension, few screening methods exist. The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Perceived Cognitive Function (PedsPCF) item bank, a 43-item parent- and self-report questionnaire, could be a useful screening tool. This study aimed to evaluate the PedsPCF item bank as a screening tool and explore its correlation with other neurocognitive measures and clinical indicators of portal hypertension. Methods Pediatric patients with portal hypertension were recruited at Lurie Children's Liver Clinic. A short battery of neuropsychological tests tapping attention, executive functioning, and fine motor speed was administered along with surveys of cognitive functioning (PedsPCF, Behavior Rating Inventory of Executive Function; BRIEF) and quality of life (PROMIS Pediatric-25 Profile). Results Eighteen patients participated (ages 8--17). The PedsPCF correlated well with the BRIEF but did not correlate with neurocognitive testing. Qualitative heatmap analysis of the relationship between z-scores and clinical signs of portal hypertension suggests the PedsPCF is less sensitive than the BRIEF. The fine motor task (Grooved Pegboard) appears to offer the highest sensitivity of the tests administered and is also relatively quick and easy to administer. Conclusions Elements of the battery show promise in this small pilot sample. The BRIEF and the Grooved Pegboard may hold the most potential for screening in the clinical setting. Further study is necessary to examine this question in a larger multicenter sample.

The review will discuss current data on neuropsychological and health-related quality of life (HRQOL) outcomes in children with liver disease. Research has trickled in over the past 30 years, mostly in small, single-center studies with observational or retrospective design. As medical treatment has advanced, survival has improved dramatically, with the majority now living into adulthood. The focus is shifting toward more systematic exploration of functional outcomes.Contemporary cohorts provide evidence for increased prevalence of IQ deficits despite overall average means in children with end-stage liver disease and long after transplant. Recent studies explore specific neurocognitive domains and populations, such as pediatric acute liver failure and metabolic disorders. HRQOL is reduced in pediatric liver transplant recipients, even years later. Current research examines HRQOL in pediatric acute liver failure, infants with chronic liver disease, and specific diseases. A major psychosocial concern is the transition from pediatric to adult care, and the challenges in assessing transfer readiness.As research in functional outcomes becomes more sophisticated (more prospective, controlled, and multisite studies), richer data are available. The most comprehensive understanding of how children with liver disease fare is achieved by integrating perspectives into one picture painted by many.

To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and85 for χThere were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age.Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Clinicaltrials.gov: NCT00061828 and NCT00294684.

To determine health-related quality of life (HRQoL) and neurocognitive impairment in survivors of pediatric acute liver failure (PALF).A longitudinal prospective study was conducted. At 6 and 12 months after PALF presentation, surveys of HRQoL were completed for 2- to 19-year-olds and executive functioning for ages 2-16 years. At 12 months, patients 3-16 years of age completed neurocognitive testing. HRQoL scores were compared with a healthy, matched sample. Neurocognitive scores were compared with norms; executive functioning scores were examined categorically.A total of 52 parent-report HRQoL surveys were completed at 6 months, 48 at 12 months; 25 patients completed neurocognitive testing. The median age at 6 months was 7.9 years (range 3.5-15.0), and final diagnosis was indeterminate for 46.2% (n = 24). Self and parent-report on Pediatric Quality of Life Inventory Generic and Multidimensional Fatigue scales fell below the healthy sample at 6 months and 12 months (almost all P .001). Children reported lower mean scores on cognitive fatigue at 12 months (60.91 ± 22.99) compared with 6 months (73.61 ± 27.49, P = .006) . The distribution of Behavior Rating Inventory of Executive Function scores was shifted downward on parent-report (preschool) for all indices at 6 months (n = 14, P ≤ .003); Global Executive Composite and Emergent Metacognition at 12 months (n = 10, P = .03). Visual Motor Integration (VMI-6) Copying (mean = 90.3 ± 13.8, P = .0002) and VMI-6 Motor Coordination (mean = 85.1 ± 15.2 P = .0002) fell below norms, but full scale IQ (Wechsler Scales) and Attention (Conners' Continuous Performance Test) did not.Survivors of PALF appear to show deficits in motor skills, executive functioning, HRQoL, and evidence for worsening cognitive fatigue from 6 to 12 months following PALF presentation.

This multicenter study examined prevalence of cognitive and academic delays in children following liver transplant (LT). One hundred and forty-four patients ages 5-7 and 2 years post-LT were recruited through the SPLIT consortium and administered the Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition (WPPSI-III), the Bracken Basic Concept Scale, Revised (BBCS-R), and the Wide Range Achievement Test, 4th edition (WRAT-4). Parents and teachers completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants performed significantly below test norms on intelligence quotient (IQ) and achievement measures (Mean WPPSI-III Full Scale IQ = 94.7 ± 13.5; WRAT-4 Reading = 92.7 ± 17.2; WRAT-4 Math = 93.1 ± 15.4; p < 0001). Twenty-six percent of patients (14% expected) had 'mild to moderate' IQ delays (Full Scale IQ = 71-85) and 4% (2% expected) had 'serious' delays (Full Scale IQ ≤ 70; p < 0.0001). Reading and/or math scores were weaker than IQ in 25%, suggesting learning disability, compared to 7% expected by CDC statistics (p < 0.0001). Executive deficits were noted on the BRIEF, especially by teacher report (Global Executive Composite = 58; p < 0.001). Results suggest a higher prevalence of cognitive and academic delays and learning problems in pediatric LT recipients compared to the normal population.

School performance is an important aspect of functional outcomes for pediatric liver transplant (LT) recipients. This longitudinal analysis conducted through the Studies of Pediatric Liver Transplantation (SPLIT) research consortium examines several indicators of school function in these patients. A total of 39 centers participated in data collection using a semistructured questionnaire designed specifically for this study. The survey queried school attendance, performance and educational outcomes including the need for special educational services. Participants included 823 of 1133 (73%) eligible patients, mean age 11.34 ± 3.84 years, 53% female, median age at LT 4.6 (range 0.05-17.8) years, and mean interval from transplant was 5.42 ± 2.79. Overall, 34% of patients were receiving special educational services and 20% had repeated a grade, with older participants more likely to have been held back (P = 0.0007). Missing more than 10 days of school per year was reported by one-third of the group, with this level of absence being more common in older participants (P = 0.0024) and children with shorter intervals from LT (P < 0.0001). Multivariate analysis revealed the following factors were associated with the need for special educational services; type of immunosuppression at 6 months post-LT, cyclosporine A (odds ratio [OR] = 1.8, confidence interval [CI] = 1.1-3.1), or other (OR = 4.9, 95% CI = 1.4-17.6) versus tacrolimus, symptomatic cytomegalovirus infection within 6 months of liver transplantation (OR = 3.1, CI = 1.6-6.1), and pretransplant special educational services (OR = 22.5, CI = 8.6-58.4). Liver Transpl 16:1041–1048, 2010. © 2010 AASLD.

Cognitive development and school function are important psychosocial outcomes that should be monitored closely in children following transplantation. This review includes discussion of a small number of studies published within the past year and details future directions in this area of research.An analysis of school-aged kidney transplant recipients revealed normal intelligence, but suggested significant impairment in gross motor and fine motor skills. Another study of adults who received kidney transplantation as children revealed that these patients rated their quality of life relatively high despite ongoing medical problems, delayed educational goals and a higher rate of unemployment than the general population. Psychoeducational outcomes of 30 pediatric liver transplant recipients who had onset of chronic liver disease in early infancy revealed that 27% of the group had intelligence scores that were more than 2 standard deviations below test norms. Progress in studying these outcomes in heart and intestinal transplant recipients has been slow and there was no new report published in this time frame.There are considerable gaps in our knowledge of these types of outcomes, but current studies support neurocognitive delay as an important problem for children receiving organ transplantation.

Although it is widely assumed that children with learning disabilities have “sequencing problems,” these have not been well specified. A non-verbal serial reaction time (SRT) paradigm was used to evaluate motor sequence learning in 422 children between ages 7 and 11 in relation to reading, cognitive ability level, and attention problems. The children demonstrated the response profile typically associated with motor sequence learning, but the component of the profile indicative of implicit sequence learning was not reliably associated with any of the predictors. Cognitive ability predicted overall response time; cognitive ability, reading, and attention problems each predicted overall accuracy. Explicit learning was predicted by cognitive ability, but not by reading or attention problems. Thus, we found no evidence that poor reading is preferentially associated with a domain general deficit in sequential learning.

Children with learning difficulties have an increased prevalence of psychosocial adjustment problems. We hypothesized that within the context of a risk and resilience model contextual variables influence adjustment, over and above any effects of academic performance. The Behavior Assessment System for Children (BASC) was used to evaluate the relationship between psychosocial adjustment, changes in academic skills, and contextual factors longitudinally over a two–year period in 100 children (ages 7 to 11) referred for learning problems. Although there was little improvement in academic skills, contextual factors contributed to observed psychosocial outcome. Different factors were salient for parents, teachers, and children. Context–derived vulnerability and protective factors can be important determinants of adjustment in children with learning problems, even though the academic difficulties can remain chronic.

Pediatric acute liver failure (PALF) is a rare but serious event, with poorly understood functional outcomes. The goal was to determine the prevalence of reduced neuropsychological functioning and health-related quality of life (HRQOL) following PALF.This multicenter study examined neuropsychological functioning and HRQOL 1 to 6 (median 3.8) years after PALF. Participants ages 6 to 16 (median 9.9) years were recruited from the PALF registry and administered measures of intelligence, visual spatial/visual motor coordination, attention, executive function, depression, and adaptive skills. HRQOL and fatigue were assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and PedsQL Multidimensional Fatigue Scale.A total of 36 patients participated; 50% were boys and 67% were white. Median age at PALF was 5.6 years. A history of grade 3 or 4 hepatic encephalopathy was reported in 5/36 (14%) participants and 23/36 (64%) received a liver transplant. Visual spatial ability was significantly better than norms (P = 0.009), but motor coordination was worse (P = 0.04). Teachers (P = 0.04 to P 0.0001) and parents (P = 0.005) reported more executive deficits versus norms, and participants had worse attention (P = 0.02). Participants did not differ significantly from norms on IQ, depression, or adaptive functioning. All of the child self-report PedsQL Generic Core and fatigue scales were significantly lower than a matched healthy sample (P = 0.001 to P 0.0001) and parent proxy report was lower on the fatigue scales (P = 0.001 to P 0.0001).Long-term PALF survivors demonstrate average IQ and visual spatial ability, but greater than expected impairments in motor skills, attention, executive function, HRQOL, and fatigue.

Morbidity associated with chronic liver disease affects the psychosocial and health-related quality of life (HRQOL) of patients and their families. Pediatric patients with liver disease demonstrate deficits in IQ that typically persist even after liver transplantation. This may be related to prolonged hospitalizations and malnutrition that often occur in this population. Research on other cognitive domains are ongoing but have demonstrated similar deficits. The chronicity of liver disease negatively affects both patients and their families through frequent hospitalizations and procedures as well as emotional and behavioral problems at home. HRQOL remains below that of the general population with school function of particular concern.

The purpose of this study was to determine whether there is a relationship between the efficiency of interhemispheric communication (IHC) and the ability to sustain attention. Children were tested on a vigilance task in which the amount of time between target presentations (interstimulus intervals; ISI) was varied. IHC was assessed by comparing within-field and between-field matches on a tachistoscopic task. Subjects who showed better IHC had faster RTs on the long ISI trials of the vigilance task, suggesting callosal involvement in the ability to sustain attention over a long period of time in the absence of sensory input.

The PedsQL™ (Pediatric Quality of Life Inventory™) is a modular instrument designed to measure health-related quality of life and disease-specific symptoms. The PedsQL™ Cognitive Functioning Scale was developed as a brief generic symptom-specific instrument to measure cognitive functioning. The objective of the present study was to determine the feasibility, reliability, and validity of the PedsQL™ Cognitive Functioning Scale in pediatric liver transplant recipients.The 6-item PedsQL™ Cognitive Functioning Scale and the PedsQL™ 4.0 Generic Core Scales were completed by pediatric liver transplant recipients ages 8-18 years (n = 215) and parents of pediatric liver transplant recipients ages 2-18 years (n = 502). Both patient self-report and parent proxy-report were available for 212 cases. The 72-item Behavior Rating Inventory of Executive Function (BRIEF), a widely validated measure of executive functioning, was completed by 100 parents and 56 teachers on a subset of patients.The PedsQL™ Cognitive Functioning Scale demonstrated minimal missing responses (0.0%, child report, 0.67%, parent report), achieved excellent reliability (α = 0.88 child report, 0.94 parent report), distinguished between pediatric patients with liver transplants and healthy children supporting discriminant validity, and was significantly correlated with the PedsQL™ 4.0 Generic Core Scales and the BRIEF supporting construct and concurrent validity, respectively. Pediatric liver transplants recipients experienced cognitive functioning comparable to long-term pediatric cancer survivors.The results demonstrate the feasibility, reliability, discriminant, construct, and concurrent validity of the PedsQL™ Cognitive Functioning Scale in pediatric liver transplant recipients.

To determine the evolution of cognitive and academic deficits and risk factors in children after liver transplantation.Patients ≥2 years after liver transplantation were recruited through Studies of Pediatric Liver Transplantation. Participants age 5-6 years at Time 1 completed the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wide Range Achievement Test, 4th edition, and Behavior Rating Inventory of Executive Function (BRIEF). Participants were retested at age 7-9 years, Time 2 (T2), by use of the Wechsler Intelligence Scales for Children, 4th edition, Wide Range Achievement Test, 4th edition, and BRIEF. Medical and demographic variables significant at P ≤ .10 in univariate analysis were fitted to repeated measures modeling predicting Full Scale IQ (FSIQ).Of 144 patients tested at time 1, 93 (65%) completed T2; returning patients did not differ on medical or demographic variables. At T2, more participants than expected had below-average FSIQ, Verbal Comprehension, Working Memory, and Math Computation, as well as increased executive deficits on teacher BRIEF. Processing Speed approached significance. At T2, 29% (14% expected) had FSIQ = 71-85, and 7% (2% expected) had FSIQ ≤70 (P = .0001). A total of 42% received special education. Paired comparisons revealed that, over time, cognitive and math deficits persisted; only reading improved. Modeling identified household status (P.002), parent education (P.01), weight z-score at liver transplantation (P.03), and transfusion volume during liver transplantation (P.0001) as predictors of FSIQ.More young liver transplantation recipients than expected are at increased risk for lasting cognitive and academic deficits. Pretransplant markers of nutritional status and operative complications predicted intellectual outcome.