Portal de Periódicos da CAPES

Assessment of Psychoeducational Outcomes After Pediatric Liver Transplant

2008; Elsevier BV; Volume: 9; Issue: 2 Linguagem: Inglês

10.1111/j.1600-6143.2008.02480.x

1600-6143

Susan Gilmour, Robin Adkins, Glennis A. Liddell, Gian S. Jhangri, Charlene M.T. Robertson,

Childhood Cancer Survivors' Quality of Life

Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 ± 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70–84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R2 = 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R2 = 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ). Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 ± 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70–84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R2 = 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R2 = 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ). Advances in medical and surgical techniques in organ transplantation now enable long-term survival for pediatric recipients (1Wallot MA Mathot M Janssen M et al.Long-term survival and late graft loss in pediatric liver transplant recipients—a 15 year single centre experience..Liver Transpl. 2002; 8: 615-622Crossref PubMed Scopus (104) Google Scholar). A growing consensus ensues, however, that mortality and morbidity measurements are an incomplete assessment of advancing medical procedures and treatment. The focus now turns to the need for more functional measures of outcomes such as development and cognitive performance (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar). The transplantation process exposes a child to a multitude of factors that may impact developmental outcome. As infancy is one of the most vulnerable periods for the developing neurological system, children diagnosed with infantile-onset liver disease are at increased risk for insult to the developing brain (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar,4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar). Malnutrition, resulting from chronic liver disease, metabolic derangements, as well as exposure to neurotoxic medications used in the transplantation process may negatively impact the growing brain (5Patchell RA Neurological complications of organ transplantation..Ann Neurol. 1994; 36: 688-703Crossref PubMed Scopus (158) Google Scholar,6Granthum-McGregor S A review of the studies of the effect of severe malnutrition on mental development..J Nutr. 1995; 125: 2233S-2238SCrossref PubMed Google Scholar). This study details the developmental, cognitive and school performance outcomes in a cohort of children with infantile-onset chronic liver disease, who were transplanted at less than or equal to 6 years of age. The study also identifies modifiable and nonmodifiable variables that may contribute to the developmental and cognitive delay. Between 1990 and 2001, 64 children received a liver transplant at the University of Alberta Hospital (Edmonton, Alberta, Canada). Forty-two children met the eligibility criteria of: (1Wallot MA Mathot M Janssen M et al.Long-term survival and late graft loss in pediatric liver transplant recipients—a 15 year single centre experience..Liver Transpl. 2002; 8: 615-622Crossref PubMed Scopus (104) Google Scholar) infantile onset of chronic end-stage liver disease, (2Hack M et al.Consideration of the use of health status, functional outcomes and quality of life to monitor neonatal intensive care practice..Pediatric. 1999; 103: 319-323Crossref PubMed Google Scholar) transplanted ≤6 years of age and (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar) continued to be followed at the University of Alberta Hospital or designated referral site. Children were excluded if they had fulminant liver failure, tumors or other disorders (e.g. inborn errors of metabolism) contributing to developmental/cognitive delay. Participating diagnoses included biliary atresia (n = 21), α-1-antitrypsin deficiency (n = 3), neonatal hepatitis (n = 4) and Alagille’s syndrome (n = 2). Five of the children died less than 6 months following transplant. Two families refused to participate and five were lost to follow-up. The final study population involved 30 children, or 81% of 37 survivors. Ethics approval was obtained from the Health Research Ethics board, University of Alberta. Signed consent was obtained at the time of evaluation. Follow-up and testing occurred at least 1-year posttransplant. Patients were contacted either prior to their annual follow-up or immediately posttransplant for follow-up at 1-year. Variables identified as ‘predictive’ for developmental/cognitive delay were selected based on transplant literature (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar, 4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar, 5Patchell RA Neurological complications of organ transplantation..Ann Neurol. 1994; 36: 688-703Crossref PubMed Scopus (158) Google Scholar, 6Granthum-McGregor S A review of the studies of the effect of severe malnutrition on mental development..J Nutr. 1995; 125: 2233S-2238SCrossref PubMed Google Scholar, 7Stewart SM Kennard BD Walter DA Fixler D Cognitive function in children who receive organ transplantation..Health Psychol. 1994; 13: 3-13Crossref PubMed Scopus (32) Google Scholar, 8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar) and clinical hypotheses. Variables were grouped according to pretransplant or posttransplant factors. Pretransplant variables included gender, socioeconomic status, height and weight percentiles, disease etiology, disease severity, lowest serum albumin, highest serum ammonia and age at transplant. Posttransplant variables included number of significant infections, episodes of rejection, surgical complications and number of days of elevated calcineurin inhibitor. Between 1990 and 1996, standard immunosuppression included cyclosporin A, azothioprine and prednisone. This regimen was changed in 1997 to tacrolimus and prednisone with a corticosteroid taper 6 to 12 months posttransplant. Elevated calcineurin inhibitor was defined as a cyclosporine A trough level greater than 450 mcg/L or a tacrolimus level greater than 15 mcg/L, as per protocol. All acute care information was obtained from medical charts or from the University of Alberta Hospital Liver Transplant Program data base. Follow-up testing was completed at the Neonatal and Infant Follow-Up Clinic, Glenrose Rehabilitation Hospital, Edmonton, Alberta. All study participants underwent a detailed general and neurological examination and audiology testing to exclude other causes of poor test results. Developmental/psychological and educational measures, as well as the semistructured adaptive behavior questionnaire, were carried out by experienced pediatric psychologists, certified for reliability and unaware of the underlying medical reason for assessment. Due to the nature of the tests used, that is neurodevelopmental and intelligence, results are grouped for those younger (up to 42 months of age) and those older (over 47 months of age). Children 3.5 to 4 years of age were not tested as the Wechsler testing for this age group is less accurate. Five children were randomly selected 1 year after assessment to repeat their Wechsler measurement to examine their stability of cognitive function posttransplant The Bayley Scales of Infant Development II (BSID—II) (9Bayley N. Manual: Bayley Scales of Infant Development. 2nd Ed. Chap. 5 and 6. San Antonio: The Psychological Corporation, 1993.Google Scholar) were chosen as the main standardized measure for children up to 3.5 years of age because of their widely accepted use and precision. This provides a mental index (MDI), or developmental quotient (DQ). Wechsler Preschool and Primary Scales of Intelligence—Revised(WPPSI-R) (10Wechsler D. Manual for the Wechsler Preschool and Primary Scale of Intelligence – Revised (WPPSI-R). Chap. 5 and 6. San Antonio: The Psychological Corporation, 1989.Google Scholar) provides standardized intellectual quotients (IQ) for children between 4 and 7.25 years of age. For older children, the Wechsler Intelligence Scale for Children-III (11Wechsler D. Manual for the Wechsler Intelligence Scale for Children-III. Chap. 5 and 6. New York: The Psychological Corporation, 1991.Google Scholar) was utilized. The Wechsler Individual Achievement Test (WIAT) (12Wechsler D. Manual for the Wechsler Individual Achievement Test. Chap. 5. San Antonio: The Psychological Corporation, 1992.Google Scholar), which records school-related achievement scores for children 5 to 19 years of age, was administered to all children of school age. The WIAT represents a composite of typical curriculum specifications (reading, mathematics and language arts). The written expression test was not used as it is only valid for grade 3 and up. Learning disability is defined by a score more than one standard deviation from the FSIQ score on one or more of the three composite scores of the WIAT. The Visual Motor Integration Test (VMI) (13Beery KE. Manual for the Developmental Test of Visual-Motor Integration. Third Revision. Chap. 5. Cleveland (OH): Modern Curriculum Press, 1989.Google Scholar) measures the ability of children, 2.8 to 18 years of age, to copy geometric designs. It is considered an important skill in the young child learning to print and write. Vineland Adaptive Behavior Scale(VABS) (14Sparrow SS, Balla DA, Ciccetti DV. Vineland Adaptive Behavior Scales, Interview Edition. Survey Form Manual. Circle Pines, MN: American Guidance Services, 1984.Google Scholar)—is a semistructured interview that assesses social competence. The VABS provides a composite score of adaptive behavior in communication, daily living skills and socialization. The latter two domains provide additional information about the children not found in the cognitive scores. For all measures the mean is 100 and standard deviation (SD) is 15. Blishen(15Blishen BR Carroll WK Moore C The 1981 socioeconomic index for occupations in Canada..Can Rev Soc Anth. 1987; 24: 465-488Crossref Scopus (629) Google Scholar), is an indicator of socioeconomic status, based on employment, education and prestige associated with the employment. Statistical analysis was performed with SPSS 12.0. All results of developmental/cognitive function and the predictive variables were analyzed assessing the mean, SD and range. Student’s t-test and chi-square analysis were utilized to assess differences between different subsets of the cohort. Analysis of variance (ANOVA) was performed to assess the three groups of patients with respect to predictive variables, participating patients, the patients who died and those lost to follow-up. Regression and correlation analysis were performed with the DQ/FSIQ, FSIQ, PIQ, VIQ and Beery scores as the continuous dependent variable with the continuous pre-, peri- and posttransplant practice variables; age at transplant, socioeconomic status, as measured by the Blishen Index, height percentile, weight percentile, serum albumin, serum ammonia, number of days of elevated calcineurin inhibitor (CI), number of significant infections, number of surgical complications, number of episodes of rejection, as independent variables. Predictive variables were included in the final multivariate analysis if the univariate analysis demonstrated a p < 0.2. Only variables or combination of variables with a p-value of ≤ 0.05 are reported in the final multivariate model. The predictive practice variables of gender and diagnosis were dichotomous and were analyzed with chi-square analysis. Patient characteristics are presented in Tables 1 and 2. Characteristics of the patients who died or were lost to follow-up are presented in Table 2. The only significant difference between the children who died or were lost to follow-up and those who participated is gender (p = .048) with a higher proportion of males in the lost to follow-up group. There was no difference in any pretransplant variables between those who were followed and those who died or were lost to follow-up. There was a difference in the number of hospitalizations between those who participated and the five children who died (p < 0.05, Scheffe post hoc analysis of ANOVA) (Table 2). The children who died had fewer pretransplant hospitalizations.Table 1Descriptive characteristics of 30 children who had infantile-onset chronic liver disease and were transplanted at ≤ 6 yearsGender20 females; 10 malesSES (Blishen (15))42 (range 21–76)(Canadian mean 43)Etiology21 biliary atresia, 9 otherMedian age at transplant1 year 5 months (rang 3 months–6 years)Status at transplant21 at home; 9 hospitalizedMean time elapsed since transplant3 years 2 months (range 6 months–12 years) Open table in a new tab Table 2Descriptive pretransplant variables of 30 assessed and 12 not assessed children after liver transplant at ≤ 6 years of age: n(%), mean ± SDPretransplant variablesAssessment status of childrenANOVA or chi-square analysisp-ValueTotal n = 42Assessed n = 30Lost n = 7Death n = 5Gender: male19 (45%)10 (33%)5 (71%)1Denotes difference from those assessed.4 (80%)1Denotes difference from those assessed.6.112Chi-square.0.05Socioeconomic status41 ± 1642 ± 1747 ± 1635 ± 130.790.46Height: <5th percentile17 (40%)9 (30%)5 (71%)3 (60%)4.940.31Weight: <5th percentile6 (38%)8 (27%)5 (71%)3 (60%)5.970.29Diagnosis: biliary atresia31 (74%)21 (70%)6 (86%)4 (80%)0.842Chi-square.0.66No. of hospitalizations1.9 ± 1.62.3 ± 1.61.3 ± 1.50.4 ± 0.91Denotes difference from those assessed.4.310.02Serum albumin g/L: lowest30 ± 829 ± 929 ± 533 ± 40.610.55Serum ammonia umol/L: highest45 ± 4849 ± 5540 ± 2228 ± 180.420.66Age at transplant: years2.1 ± 1.72.2 ± 1.81.8 ± 1.91.6 ± 0.70.320.731 Denotes difference from those assessed.Label Chi-square. Open table in a new tab As noted from Table 1, Table 2, Table 3, the assessed cohort is mostly between 1 to 2 years of age (mean 1 year 5 months) at the time of transplant. Children were evaluated at a mean of 3 years 2 months posttransplant. They have an average socioeconomic status (15Blishen BR Carroll WK Moore C The 1981 socioeconomic index for occupations in Canada..Can Rev Soc Anth. 1987; 24: 465-488Crossref Scopus (629) Google Scholar). Highest recorded serum ammonia levels were slightly elevated (mean 48 lmol/L ± 55) and lowest serum albumin pretransplant was a mean of 29 g/L ± 8.6. Most patients were hospitalized at least twice prior to transplant (mean number of hospitalizations 2.3 ± 1.5). Postoperatively, most patients experienced episodes of rejection (mean number episodes 1.4 ± 1.6), days of elevated calcineurin inhibitors (mean number of days 8 ± 6.5) and episodes of infection (mean 3.4 ± 3.7), with relatively few having surgical complications, including hemorrhage, bile leaks, strictures or infection, or required a repeat laparotomy (mean 0.77 ± 1.2). Due to the age range of the participants, 10 children ( 47 months of age) had Wechsler testing (WPPSI-R, WISC-III) and Beery. The 20 older children have more extensive results, including a fullscale score IQ (FSIQ), a performance IQ (PIQ), verbal IQ (VIQ) and Beery (visual motor integration). A comparison of the younger (n = 10) and older (n = 20) was performed with student’s t-test and chi-square to assess for any difference between the two groups. There were no significant differences between the groups in development/cognitive test scores, VABS (composite and subsections) score and all predictive variables (Tables 3 and 4).Table 3Pre- and posttransplant variables for 30 assessed younger (BSID-II and older (WPSSI-R, WISC-III) children after liver transplantation at ≤6 years of age: n (%), mean ± SDVariablesAssessment age (months)t-statistic or chi-squarep-ValueTotal n = 30 47 n = 20PretransplantGender: male10 (33%)5 (50%)5 (25%)1.880.17Socioeconomic status (15Blishen BR Carroll WK Moore C The 1981 socioeconomic index for occupations in Canada..Can Rev Soc Anth. 1987; 24: 465-488Crossref Scopus (629) Google Scholar)42 ± 1743 ± 1441 ± 190.200.82Height percentile21 ± 2828 ± 3518 ± 230.280.79Weight percentile22 ± 2821 ± 2722 ± 29−0.480.64Diagnosis: biliary atresia21 (70%)6 (60%)15 (75%)0.430.52No. of hospitalizations2.3 ± 1.61.7 ± 1.12.7 ± 1.7−1.590.12Serum albumin g/L: lowest29 ± 926 ± 831 ± 90.970.32Serum ammonia umol/L: highest49 ± 5559 ± 7743 ± 42−1.490.15PosttransplantNo. of infections3.4 ± 3.73.2 ± 3.13.1 ± 4.0−0.900.38No. of surgical complications0.8 ± 1.21.1 ± 1.60.6 ± 0.9−1.200.24No. of episodes of elevated calcineurin inhibitor8 ± 6.59.5 ± 7.77.2 ±5.80.080.94No. of rejections1.4 ± 1.61.4 ± 1.21.4 ± 1.8−1.70.10 Open table in a new tab Table 4Psychological test results for 30 assessed younger and older children after liver transplantation at ≤6 years of age: mean ± SD.Outcome variableAssessment age (months)t-testp-Value 47 n = 20Developmental quotient/intelligence quotient75 ± 2084 ± 15−1.350.19Performance intelligence quotientna86 ± 19Verbal intelligence quotientna84 ± 13Vineland adaptive behavior scalesCommunication85 ± 1890 ± 17−0.840.42Daily living85 ± 1594 ± 15−1.600.12Socialization99 ± 20104 ± 12−0.890.38Motor85 ± 1998 ± 18−1.830.08Composite85 ± 1793 ± 17−1.1420.26Visual motor integrationna82 ± 12Reference means = 100 ± 15 (9−11). Open table in a new tab Reference means = 100 ± 15 (9−11). Patients with biliary atresia did demonstrate a higher DQ/IQ compared to other diagnosis, 85.1 ± 16.9 versus 71.0 ± 14.2 (p = 0.036). The mean DQ score (n = 10) was 75 and the mean FSIQ was 84. The result of the combined DQ/FSIQ was 81 ± 17. The range of scores varied from the lowest possible score of 49 to a high score of 121. Population normal values are 100 ± 15, with 70 being delayed (the clinical definition of mental retardation) and 70–84 borderline delayed (Figure 1). The cognitive results were stable over time in the five reassessed children, time one versus time two, p = 0.091, Wilcoxon sign-rank test. Examining specific aspects of cognitive/brain function, reveals that the mean PIQ was 86 ± 19 and the VIQ 84 ± 13. Visual motor integration as screened with the Beery had a mean of 82 ± 12. School achievement: Eleven children were an appropriate age and developmental status to complete subject specific testing with the WIAT. The subject scores, standard deviations and score ranges are displayed in Table 5. This subset of patients demonstrated specific patterns of deficit. Mathematics scores were poor, mean = 74 ± 13, with only two patients with a composite math score greater than 85. Numeric operations demonstrated the greatest impairment, mean = 74 ± 10.Table 5School achievement scores of 11 children after liver transplant at ≤6 years of age: mean ± SD, n (%)AchievementScore mean ± SDNumber (%) of children with abnormal scores1Abnormal score is a standard score of <85. (n = 11)Composite reading85 ± 183 (27%)Basic reading92 ± 162 (18%)Reading comprehension82 ± 156 (55%)Listening comprehension86 ± 168 (73%)Composite mathematics74 ± 139 (82%)Mathematics reasoning80 ± 138 (73%)Numeric operations74 ± 106 (55%)Spelling91 ± 174 (36%)1 Abnormal score is a standard score of <85. Open table in a new tab The Vineland Adaptive-Behavior Scales, as reported by the primary care provider, range from 88 to 102 (Table 4). Socialization is the only totally preserved domain. The results of the VABS communication and composite scores differ from the DQ/FSIQ scores and did not demonstrate correlation (Pearson correlation VABS communication p = 0.07, VABS composite p = 0.371). Regression analysis examining variables predictive of developmental/cognitive delay (DQ/FSIQ), delay of PIQ, VIQ, Beery and VABS demonstrated some distinctive patterns. For the combined DQ/FSIQ, the diagnosis of biliary atresia was associated with a higher DQ/FSIQ and accounted for 14.7% of the variance (Table 6). The subset of children who had Wechsler testing (n = 20) found that almost 32% (Table 6) of the FSIQ variance was associated with the variables of decreased height pretransplant and increasing days of elevated trough serum calcineurin inhibitor levels.Table 6Multiple regression analysis for predictive variables and dependent outcomesOutcome variablePredictive variableSlopeStandard errorp-ValueR2DQ/FSIQBiliary atresia14.1436.4370.0360.147FSIQHeight percentile0.3040.1320.0340.319Number of days of elevated CI−0.9930.4760.050VIQNumber of days of elevated CI−0.9680.4170.0320.231PIQHeight percentile0.4810.1530.0060.445Highest serum ammonia−0.1570.0380.014BeeryHeight percentile0.2240.1010.0390.332Highest serum ammonia−0.0910.0380.027For the remaining results, n = 20.DQ/FSIQ = Combined BSID-II and Wechsler scores (n = 30) Open table in a new tab For the remaining results, n = 20. DQ/FSIQ = Combined BSID-II and Wechsler scores (n = 30) Verbal IQ results in the same 20 children also found that 23% of the variance in their verbal score can be associated with elevated calcineurin inhibitors (Table 6). Performance function as evidenced by the PIQ and Beery demonstrates different predictors of impaired cognitive subscores compared to the VIQ. The PIQ has 44.5% of its variance associated with decreased pretransplant height and highest measured serum ammonia. The Beery has the same predictors with 33% of variance due to the same variables. Note that socioeconomic status is not a predictive variable for DQ/FSIQ, PIQ, VIQ, FSIQ, Beery or the VABS. Delay and borderline delay were very frequent in this cohort of children, not only in comparison to the general population but to other reported transplant cohorts (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar,4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar,7Stewart SM Kennard BD Walter DA Fixler D Cognitive function in children who receive organ transplantation..Health Psychol. 1994; 13: 3-13Crossref PubMed Scopus (32) Google Scholar,8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar,16Stewart SM Hiltebeitel C Nici J Waller DA Uauy R Andrews WS Neuropsychological outcomes of pediatric liver transplantation..Pediatric. 1991; 87: 367-376Crossref PubMed Google Scholar, 17Adeback P Nemeth A Fischler B Cognitive and emotional outcome after pediatric liver transplantation..Pediatr Transplant. 2003; 7: 385-389Crossref PubMed Scopus (54) Google Scholar, 18Gritti A Di Sarno AM Comito M DeVincenzo A DePaola P Vajro P Psychological impact of liver transplantation on children’s inner world..Pediatr Transplant. 2001; 5: 37-43Crossref PubMed Scopus (42) Google Scholar, 19Schultz KH Wein C Boeck A Rogiers X Burdelski M Cognitive performance of children who have undergone liver transplantation..Transplantation. 2003; 75: 1236-1240Crossref PubMed Scopus (41) Google Scholar, 20Kennard BD Stewart SM Phelan-McAuliffe D et al.Academic outcome in long-term survivors of pediatric liver transplantation..J Dev Behav Pediatr. 1999; 20: 17-23Crossref PubMed Scopus (66) Google Scholar). The findings of 27% delayed and 27% borderline delayed with only 46% with normal intelligence is twice (borderline delayed) and 14 times (delayed) the expected normative population prevalence. School subject testing demonstrated learning deficits in all subject areas but most profound in mathematics, especially numeric operations. The study demonstrated that variables predictive of developmental/cognitive impairment differed depending upon the area of cognition; performance (PIQ) and verbal (VIQ) domains. The older children who had Wechsler testing (n = 20) had their impaired composite FSIQ associated with growth failure and increased days of high-trough cal-cineurin inhibitors levels. The FSIQ predictive variables are reflected in the variables associated in the combined subscales of with a lower PIQ associated with impaired growth and elevated serum ammonia and lower VIQ associated with elevated calcineurin inhibitor levels. Confirming the association with PIQ, a separate measure, the Beery, component of performance, was also associated with impaired growth and elevated calcineurin inhibitors. The diagnosis of biliary atresia was associated with a better DQ/FSIQ score. This association may be attributed to the confounding issue of other etiologies potential association of cognitive delay, or alternatively, the natural history of biliary atresia is so well known that this may result in patients being transplanted at a different stage of end-stage liver failure. Unfortunately, the easily administered parental questionnaire, the VABS, somewhat underestimated the measured mental/cognitive delay. However, the parents of the younger children did place their children one standard deviation below normal for communication. It was interesting to note that, despite multiple hospitalizations and significant life-threatening disease parents report the VABS socialization domain to be preserved. Compared to previous studies, there were many unique results. Most striking was our higher rate of delay (27%) and borderline delay (27%). Others have demonstrated mean FSIQ of 86–94 with a prevalence of delay between 5% and 24% (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar,4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar,8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar,11Wechsler D. Manual for the Wechsler Intelligence Scale for Children-III. Chap. 5 and 6. New York: The Psychological Corporation, 1991.Google Scholar, 12Wechsler D. Manual for the Wechsler Individual Achievement Test. Chap. 5. San Antonio: The Psychological Corporation, 1992.Google Scholar, 13Beery KE. Manual for the Developmental Test of Visual-Motor Integration. Third Revision. Chap. 5. Cleveland (OH): Modern Curriculum Press, 1989.Google Scholar, 14Sparrow SS, Balla DA, Ciccetti DV. Vineland Adaptive Behavior Scales, Interview Edition. Survey Form Manual. Circle Pines, MN: American Guidance Services, 1984.Google Scholar, 15Blishen BR Carroll WK Moore C The 1981 socioeconomic index for occupations in Canada..Can Rev Soc Anth. 1987; 24: 465-488Crossref Scopus (629) Google Scholar, 16Stewart SM Hiltebeitel C Nici J Waller DA Uauy R Andrews WS Neuropsychological outcomes of pediatric liver transplantation..Pediatric. 1991; 87: 367-376Crossref PubMed Google Scholar, 17Adeback P Nemeth A Fischler B Cognitive and emotional outcome after pediatric liver transplantation..Pediatr Transplant. 2003; 7: 385-389Crossref PubMed Scopus (54) Google Scholar, 18Gritti A Di Sarno AM Comito M DeVincenzo A DePaola P Vajro P Psychological impact of liver transplantation on children’s inner world..Pediatr Transplant. 2001; 5: 37-43Crossref PubMed Scopus (42) Google Scholar, 19Schultz KH Wein C Boeck A Rogiers X Burdelski M Cognitive performance of children who have undergone liver transplantation..Transplantation. 2003; 75: 1236-1240Crossref PubMed Scopus (41) Google Scholar, 20Kennard BD Stewart SM Phelan-McAuliffe D et al.Academic outcome in long-term survivors of pediatric liver transplantation..J Dev Behav Pediatr. 1999; 20: 17-23Crossref PubMed Scopus (66) Google Scholar). Our cohort had a mean FSIQ of 84 and when combined a mean DQ/FSIQ of 81. These results are more in keeping with recent cohorts such as Adeback’s, describing a mean FSIQ of 86 than compared to the older cohorts of Stewart that demonstrated less cognitive delay (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar,17Adeback P Nemeth A Fischler B Cognitive and emotional outcome after pediatric liver transplantation..Pediatr Transplant. 2003; 7: 385-389Crossref PubMed Scopus (54) Google Scholar,20Kennard BD Stewart SM Phelan-McAuliffe D et al.Academic outcome in long-term survivors of pediatric liver transplantation..J Dev Behav Pediatr. 1999; 20: 17-23Crossref PubMed Scopus (66) Google Scholar). Similar to Kennard’s and Stewart’s cohort, our patients had greater deficits with math and some language skills, which is in contrast to others who found verbal language impairment (4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar,8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar). Unfortunately, also similar to other cohorts, the children we studied were underrecognized as cognitively delayed with only 7 of 30 (23%) children receiving early intervention or modified learning environment. The greater prevalence of delay in this group of patients may be due to its homogeneity. Only children with onset of chronic end-stage liver disease at the most neurolog- ically venerable period and young age at transplantation were recruited. This cohort’s etiology and age are typical of over 40% of the pediatric liver transplants, therefore, it is an important homogeneous group to assess (21Studies of Pediatric Liver transplantation (SPLIT) 2007 Annual Report. EMMES Corp, Rockville, MD. P 2–4, 2–6.Google Scholar). Previous studies, except for Wayman’s, used patients with far more heterogeneous age at onset of end-stage disease and age of exposure to posttransplant variables (8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar). Etiologies such as tumors, cystic fibrosis or metabolic disorders may not have the same metabolic or nutritional exposures and have other practice variables that confound the developmental/cognitive outcomes. Thus, the variable etiologies and timing of exposures in previous studies make it more difficult to assess for prevalence of delay and predictive variables. Previously, variables predictive of cognitive impairment have included growth failure, low serum albumin, high serum bilirubin and number of days in hospital during the first posttransplant year (3Stewart SM Uauy R Waller DA Kennard BD Benser M Andrews WS Mental and motor development, social competence and growth 1 year after successful pediatric liver transplantation..J Pediatr. 1989; 114: 574-581Abstract Full Text PDF PubMed Scopus (115) Google Scholar,4Krull K Fuchs C Yurk H Boone P Alonso EM Neurocognitive outcomes in pediatric liver transplant recipients..Pediatr Transpl. 2003; 7: 111-118Crossref PubMed Scopus (72) Google Scholar,8Wayman KI Cox KL Esquivel CO Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1year after liver transplantation..J Pediatr. 1997; 131: 849-898Abstract Full Text Full Text PDF Scopus (110) Google Scholar,19Schultz KH Wein C Boeck A Rogiers X Burdelski M Cognitive performance of children who have undergone liver transplantation..Transplantation. 2003; 75: 1236-1240Crossref PubMed Scopus (41) Google Scholar). Our results are similar in that growth failure was associated with impaired PIQ, visual motor integration (Beery) and FSIQ. The unique findings of this study were the distinctive patterns of variables associated with the different areas of cognition, VIQ and PIQ, and this study is the first to demonstrate an association between the posttransplant variable of elevated cal- cineurin inhibitors and impaired FSIQ and VIQ. Calcineurin inhibitor neurotoxicity is well described, with 40% of patients experiencing these effects (5Patchell RA Neurological complications of organ transplantation..Ann Neurol. 1994; 36: 688-703Crossref PubMed Scopus (158) Google Scholar). Growth failure may provide a surrogate marker for malnutrition. Studies have demonstrated that school-age children who suffered from early childhood malnutrition have generally been found to have poorer cognitive scores, school achievement and greater behavioral problems than matched controls (6Granthum-McGregor S A review of the studies of the effect of severe malnutrition on mental development..J Nutr. 1995; 125: 2233S-2238SCrossref PubMed Google Scholar). There is also a biological plausibility of elevated serum ammonia levels resulting in impaired cognition. Ammonia toxicity has been demonstrated to correlate with hepatic encephalopathy and the increasing serum levels do have a positive correlation with increasing encephalopathy (22Ong JP Aggarwal A Krieger D et al.Correlation between ammonia levels and severity of hepatic encephalopathy..Am J Med. 2001; 114: 188-193Abstract Full Text Full Text PDF Scopus (400) Google Scholar). But minor changes in portal blood flow and ammonia metabolism have been documented to diminish cognitive ability (23Mack CL Zelko FA Lokar J et al.Surgically restoring portal blood flow to the liver in children with primary extrahepatic portal vein thrombosis improves fluid neurocognitive ability..Pediatric. 2006; 117: e405-e412Crossref PubMed Scopus (86) Google Scholar). As this study represents the results of a single pediatric liver transplant centre, issues arise such as the lack of pretransplant information, some heterogeneity of the cohort including the use of both Wechsler and BSID-II measures and lack of a control population. The children in this study were recruited retrospectively posttransplant and therefore there was an inability to obtain pretransplant evaluation. Although the study was designed to evaluate variables associated with delay, the primary objective of the study was to assess the prevalence of developmental/cognitive delay and to be able to provide individual family information to access early intervention and special education programs if required. Children were assessed at variable clinically stable distances from transplant but the subset of reassessed children demonstrated the stability of their cognitive ability over time. Chronic illness in childhood has been shown to impact cognition and be associated with school limitation in more than 30% of affected children (24Msall ME Avery RC Tremont MR et al.Functional disability and school activity limitations in 41 300 school-age children: Relational to medical impairments..Pediatric. 2003; 111: 548-553Crossref PubMed Scopus (70) Google Scholar), but we specifically chose not to have a control group of another chronic illness. Children will be compared to their same age peers in school environments. So to use population normative cognitive and developmental results provides the children’s true comparative peers. Although we did not have a control group, our Infant and Child Follow-up Program has previously assessed and reported the results of infants with complex congenital heart disease and surgery. These children also had life-threatening disease and invasive therapy at a neurologically vulnerable age, but their potential predictive variables differ from children with liver disease. Robertson et al. demonstrated a similar prevalence of delay, with 25% delayed and only 50% with a normal development in this population (25Robertson CM Joffe AR Sauve RS Rebeyka IM Dyck JD Harder JR The western Canadian complex pediatric therapies project follow-up group..J Pediatric. 2004; 144: 86-92Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). This same cohort was further assessed at 5 years of age with Wechsler measures and demonstrated that the presence of delay and borderline delay with BSID-II was strongly predictive of similar Wechsler measurement results (26Creighton DE Robertson CM Sauve RS et al.Western Canadian complex pediatric therapies project follow-up group..Pediatric. 2007; 120: e478-e486Crossref PubMed Scopus (79) Google Scholar). Another point of discussion is the analysis of combined Wechsler and BSID-II measurement results. Results were presented for both the combined cohort and the two subsets. The collapsing of the two measures was done because of the inability to have one measure for all developmental age groups and the very good predictive validity of the DQ for the FSIQ in previous studies and our previous experience in the infant cardiac population (9Bayley N. Manual: Bayley Scales of Infant Development. 2nd Ed. Chap. 5 and 6. San Antonio: The Psychological Corporation, 1993.Google Scholar,26Creighton DE Robertson CM Sauve RS et al.Western Canadian complex pediatric therapies project follow-up group..Pediatric. 2007; 120: e478-e486Crossref PubMed Scopus (79) Google Scholar). Our results demonstrate more profound developmental/ cognitive impairment than previous studies but the results are on a more homogeneous cohort so all participants had similar risk factors for growth failure, low albumin, malnutrition, hyperammonemia and frequent hospitalizations. We examined children who were infants with a life-threatening chronic disease during the time of greatest neural growth, so the magnitude of our results compared to previous studies is not surprising. The goal of pediatric liver transplantation is to provide an intact survival, which includes health, quality of life, cognitive function and school performance. The concept of intact survival is usually achieved but still requires improvement. Further prospective multi centre research is required to assess the impact of improving potentially modifiable variables. The most important finding of this study has been to highlight the profound need to objectively assess develop- mental/cognitive status in all children postliver transplant as the prevalence of delay and borderline delay is much greater than previously reported. This can be achieved by enrolling all these children in long-term neurodevelopmental follow-up and will allow us to provide supports to maximize the children’s potential and their ability to succeed in school, with peers and into adulthood. This study was supported by Alberta Heritage Research Grant No. 199800110-2.