Pre-school neurocognitive and functional outcomes after liver transplant in children with early onset urea cycle disorders, maple syrup urine disease, and propionic acidemia: An inception cohort matched-comparison study.

BACKGROUND: Urea cycle disorders (UCD) and organic acid disorders classically present in the neonatal period. In those who survive, developmental delay is common with continued risk of regression. Liver transplantation improves the biochemical abnormality and patient survival is good. We report the neurocognitive and functional outcomes post-transplant for nine UCD, three maple syrup urine disease, and one propionic acidemia patient. METHODS: Thirteen inborn errors of metabolism (IEM) patients were individually one-to-two matched to 26 non-IEM patients. All patients received liver transplant. Wilcoxon rank sum test was used to compare full-scale intelligence-quotient (FSIQ) and Adaptive Behavior Assessment System-II General Adaptive Composite (GAC) at age 4.5 years. Dichotomous outcomes were reported as percentages. RESULTS: FSIQ and GAC median [IQR] was 75 [54, 82.5] and 62.0 [47.5, 83] in IEM compared with 94.5 [79.8, 103.5] and 88.0 [74.3, 97.5] in matched patients (P-value <.001), respectively. Of IEM patients, 6 (46%) had intellectual disability (FSIQ and GAC <70), 5 (39%) had autism spectrum disorder, and 1/13 (8%) had cerebral palsy, compared to 1/26 (4%), 0, 0, and 0% of matched patients, respectively. In the subgroup of nine with UCDs, FSIQ (64[54, 79]), and GAC (56[45, 75]) were lower than matched patients (100.5 [98.5, 101] and 95 [86.5, 99.5]), P = .005 and .003, respectively. CONCLUSION: This study evaluated FSIQ and GAC at age 4.5 years through a case-comparison between IEM and matched non-IEM patients post-liver transplantation. The neurocognitive and functional outcomes remained poor in IEM patients, particularly in UCD. This information should be included when counselling parents regarding post-transplant outcome.

Kindergarten-age neurocognitive, functional, and quality-of-life outcomes after liver transplantation at under 6 years of age.

BACKGROUND: We aimed to describe school-entry age neurocognitive, functional, and HRQL outcomes and their predictors after liver transplant done at age <6 years. METHODS: A prospective cohort of all (n = 69) children surviving liver transplant from 1999 to 2014 were assessed at age 55.4 (SD 7.2) months and 38.6 (12.4) months after transplant. Assessment included: the Wechsler Preschool and Primary Scales of Intelligence, Beery-Buktenica Developmental Test of VMI, Adaptive Behavior Assessment System caregiver-completed questionnaire, and PedsQL 4.0 Generic Core Scales. Univariate and multiple linear regression determined predictors of outcomes at P < .05. RESULTS: Neurocognitive and functional outcomes were on average within 1 SD of population norms, although shifted to the left (P ≤ .03), with more patients than expected having scores >2 (3.7-5.9 times more, P ≤ .007) SD below population norms. Total and Summary HRQL scores were statistically significantly lower than the healthy normative population (P ≤ .02) and a congenital heart disease group (P ≤ .02), but similar to children with other chronic health conditions; differences often exceeded the MCID and were lowest in the School functioning domain. There were few predictors on multiple linear regressions, and we could not confirm previous studies that suggested various inconsistent predictors of outcomes. Neurocognitive and functional outcomes scores were highly correlated with HRQL scores except for the School functioning domain, but did not fully explain them. CONCLUSIONS: Long-term follow-up of this vulnerable population is important in order to facilitate support for the patient and family, and early intervention for any difficulties identified.

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Neurocognitive and functional outcomes at 5 years of age after renal transplant in early childhood.

BACKGROUND: Clinicians often use information about developmental outcomes in decision-making around offering complex, life-saving interventions in children such as dialysis and renal transplant. This information in children with end-stage renal disease (ESRD) is limited, particularly when ESRD onset is in infancy or early childhood. METHODS: Using data from an ongoing prospective, longitudinal, inception cohort study of children with renal transplant before 5 years of age, we evaluated (1) the risk of adverse neurocognitive and functional outcomes at 5 years of age and (2) predictors of developmental outcomes. RESULTS: We found evidence of neurocognitive sequelae of ESRD in very young children; however, developmental outcomes appear remarkably better when compared with findings of two or three decades ago. Less time on dialysis predicted higher developmental scores, and hemodialysis was associated with poorer developmental outcomes. CONCLUSIONS: Our data suggest that renal replacement therapies in young children are associated with acceptable developmental outcome. Programs to identify those with developmental delays and provide early intervention may allow achievement of the child's full potential.

Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Neurocognitive outcomes after heart transplantation in early childhood.

BACKGROUND: Children requiring heart transplantation (HTx) for congenital heart disease (CHD) or failing anatomically normal hearts (CMP) face different challenges pre-HTx. We compared the neurocognitive capabilities in pre-school-age children receiving HTx for CHD vs CMP and determined factors predicting outcomes. METHODS: Data were collected within a prospective multi-provincial project from children who underwent HTx ≤4 years of age between 1999 and 2011. At age 54 ± 3 months, we obtained scores from the Wechsler Preschool and Primary Scales of Intelligence for full-scale intelligence quotient (FSIQ) verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), and from the Beery-Buktenica Developmental Test for visual-motor integration (VMI). Possible predictive factors were collected prospectively from transplant listing. RESULTS: Of the 76 patients included in the study, 61 survived to assessment, 2 were lost to follow-up and 4 were excluded for genetic disorders or heart-lung transplant. The CHD patients (n = 32) had significantly more previous surgeries, more severe kidney injuries, more days on ventilator and in intensive care, broader human leukocyte antigen (HLA) sensitization, longer cardipulmonary bypass (CPB) times and higher inotropic scores than CMP patients (n = 23). Mean IQ scores for the HTx children were below population norms and significantly lower in children with CHD. Intellectual disability (FSIQ <70) was more common in the CHD group (p = 0.036). The lower VMI in CHD patients approached significance. Lower FSIQ and VMI were independently associated with higher pre-HTx creatinine and lactate, longer stay in intensive care and lower socioeconomic status. CONCLUSIONS: Children post-HTx showed IQ and VMI scores within the borderline to low-average range, with CHD children ranging significantly lower. Low scores are associated with a more difficult pre- and peri-transplant course. Careful follow-up is required to warrant early detection of deficits and introduction of interventions and supportive measures.

Hypoplastic Left Heart Syndrome is not Associated with Worse Clinical or Neurodevelopmental Outcomes Than Other Cardiac Pathologies After the Norwood-Sano Operation.

There is evidence to suggest that patients undergoing a Norwood for non-HLHS anatomy may have lower mortality than classic HLHS, but differences in neurodevelopmental outcome have not been assessed. Our objective was to compare survival and neurodevelopmental outcome during the same surgical era in a large, well-described cohort. All subjects who underwent a Norwood-Sano operation between 2005 and 2014 were included. Follow-up clinical, neurological, and developmental data were obtained from the Western Canadian Complex Pediatric Therapies Follow-up Program database. Developmental outcomes were assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development (Bayley-III). Survival was assessed using Kaplan-Meier analysis. Baseline characteristics, survival, and neurodevelopmental outcomes were compared between those with HLHS and those with non-HLHS anatomy (non-HLHS). The study comprised 126 infants (75 male), 87 of whom had HLHS. Five-year survival was the same for subjects with HLHS and those with non-HLHS (HLHS 71.8%, non-HLHS 76.9%; p = 0.592). Ninety-three patients underwent neurodevelopmental assessment including Bayley-III scores. The overall mean cognitive composite score was 91.5 (SD 14.6), language score was 86.6 (SD 16.7) and overall mean motor composite score was 85.8 (SD 14.5); being lower than the American normative population mean score of 100 (SD 15) for each (p-value for each comparison, <0.0001). None of the cognitive, language, or motor scores differed between those with HLHS and non-HLHS (all p > 0.05). In the generalized linear models, dominant right ventricle anatomy (present in 117 (93%) of patients) was predictive of lower language and motor scores. Comparative analysis of the HLHS and non-HLHS groups undergoing single ventricle palliation including a Norwood-Sano, during the same era, showed comparable 2-year survival and neurodevelopmental outcomes.

Screening for language delay after life-saving therapies in term-born infants.

BACKGROUND: Strong recommendations have been made for the periodic developmental surveillance, screening, and evaluation of children with CHD. This supports similar calls for all at-risk children in order to provide timely, structured early developmental intervention that may improve outcomes. The aim of this study was to determine the accuracy of screening for language delay after life-saving therapies using the parent-completed vocabulary screen of the language Development Survey, by comparing screening with the individually administered language scores of the Bayley Scales of Infant and Toddler Development, Third edition. METHOD: In total, 310 (92.5%) of 335 eligible term-born children, born between 2004 and 2011, receiving complex cardiac surgery, heart or liver transplantation, or extracorporeal membrane oxygenation in infancy, were assessed at 21.5 (2.8) months of age (lost, 25 (7.5%)), through developmental/rehabilitation centres at six sites as part of the Western Canadian Complex Pediatric Therapies Follow-up Group. RESULTS: Vocabulary screening delay was defined as scores ⩽15th percentile. Language delay defined as scores >1 SD below the mean was calculated for language composite score, receptive and expressive communication scores of the Bayley-III. Delayed scores for the 310 children were as follows: vocabulary, 144 (46.5%); language composite, 125 (40.3%); receptive communication, 98 (31.6%); and expressive communication, 124 (40%). Sensitivity, specificity, positive predictive values, and negative predictive values of screened vocabulary delay for tested language composite delay were 79.2, 75.7, 68.8, and 84.3%, respectively. CONCLUSION: High rates of language delay after life-saving therapies are concerning. Although the screening test appears to over-identify language delay relative to the tested Bayley-III, it may be a useful screening tool for early language development leading to earlier referral for intervention.

Sepsis After Cardiac Surgery Early in Infancy and Adverse 4.5-Year Neurocognitive Outcomes.

BACKGROUND: We aimed to determine whether sepsis is associated with neurocognitive outcomes 4.5 years after congenital heart disease surgery in early infancy. METHODS AND RESULTS: A secondary analysis from a prospective inception cohort included all children having congenital heart disease surgery done at ≤6 weeks of age with cardiopulmonary bypass at the Western Canadian referral center from 1996 to 2009. Follow-up at the referral center determined the primary outcomes at 4.5 years with full-scale, performance, and verbal intelligence quotients on the Wechsler Preschool and Primary Scale of Intelligence. Perioperative variables were collected prospectively, and confirmation of blood culture-positive sepsis was done retrospectively. Multiple linear regression models for neurocognitive outcomes and multiple Cox proportional hazards regression for mortality were determined. Sepsis occurred in 97 of 502 patients (19%) overall and in 76 of 396 survivors (19%) with 4.5-year follow-up. By 4.5 years, there were 91 (18%) deaths, and 396 of 411 survivors (96%) had follow-up completed. Extracorporeal membrane oxygenation was associated with worse scores on all neurocognitive outcomes on multivariable regression; the association between extracorporeal membrane oxygenation and full-scale intelligence quotient had a regression coefficient of -13.6 (95% CI -21.3 to -5.9; P=0.001). Sepsis perioperatively was associated with performance and verbal intelligence quotients, with a trend for full-scale intelligence quotient (P=0.058) on multivariable regression. The regression coefficient for sepsis was strongest for performance intelligence quotient (-5.31; 95% CI -9.84 to -0.78; P=0.022). Sepsis was not but extracorporeal membrane oxygenation was associated with mortality by 4.5 years. CONCLUSIONS: Perioperative sepsis and extracorporeal membrane oxygenation were associated with adverse neurocognitive outcomes on multivariable regression. Quality improvement to prevent sepsis has the potential to improve long-term neurocognitive outcomes in infants after surgery for congenital heart disease.

Neurocognitive outcomes at kindergarten entry after liver transplantation at <3 yr of age.

This prospective inception cohort study determines kindergarten-entry neurocognitive abilities and explores their predictors following liver transplantation at age <3 yr. Of 52 children transplanted (1999-2008), 33 (89.2%) of 37 eligible survivors had psychological assessment at age 54.7 (8.4) months: 21 with biliary atresia, seven chronic cholestasis, and five acute liver failure. Neurocognitive scores (mean [s.d.], 100 [15]) as tested by a pediatric-experienced psychologist did not differ in relation to age group at transplant (≤12 months and >12 months): FSIQ, 93.9 (17.1); verbal (VIQ), 95.3 (16.5); performance (PIQ), 94.3 (18.1); and VMI, 90.5 (15.9), with >70% having scores ≥85, average or above. Adverse predictors from the pretransplant, transplant, and post-transplant (30 days) periods using univariate linear regressions for FSIQ were post-transplant use of inotropes, p = 0.029; longer transplant warm ischemia time, p = 0.035; and post-transplant highest serum creatinine, (p = 0.04). For PIQ, they were pretransplant encephalopathy, p = 0.027; post-transplant highest serum creatinine, p = 0.034; and post-transplant inotrope use, p = 0.037. For VMI, they were number of post-transplant infections, p = 0.019; post-transplant highest serum creatinine, p = 0.025; and lower family socioeconomic index, p = 0.039. Changes in care addressing modifiable predictors, including reducing acute post-transplant illness, pretransplant encephalopathy, transplant warm ischemia times, and preserving renal function, may improve neurocognitive outcomes.

Overestimating neurodevelopment using the Bayley-III after early complex cardiac surgery.

BACKGROUND: The newest measure of neurodevelopmental outcomes, the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III), gives higher-than-expected scores for preterm infants; results after cardiac surgery are unknown. OBJECTIVES: The goal of this study was to report Bayley-III scores after cardiac surgery and compare the results with those of the Bayley Scales of Infant Development, 2nd Edition (BSID-II) on a subset of the same children. METHODS: In this prospective, inception cohort, neurodevelopmental outcome study after complex cardiac surgery in infants from 2004 to 2007, the Bayley-III was given to 110 survivors (68% boys) at a mean age of 21 months (SD: 4 months). Analysis of variance was used to compare intergroup differences. Results for both test editions on the same 25 children were compared by using paired-samples statistics. RESULTS: Mean (SD) Bayley-III mean composite scores (CSs) for 110 children were as follows: cognitive, 95.9 (14.1); language, 90.8 (18.1); and motor, 93.7 (14.2), differentiating selected cardiac surgery groups. The average difference in mean CSs was 7.4 points higher than BSID-II scores for a previous cohort from this site and 7.2 points higher than a systematic review report. Direct comparison of BSID-II and Bayley-III revealed an average difference in mean CSs of 6.1 points, similar to normative results. Mean cognitive CSs increased by 10.0 (P <.001), language by 1.4 (P = .526), and motor by 6.9 points (P = .009). CONCLUSIONS: Researchers should be careful attributing higher Bayley-III scores to changes in acute care. At-risk children who previously qualified for early developmental intervention may no longer do so. School-age longitudinal studies are needed to determine the accuracy of early developmental estimates using the Bayley-III.

Outcomes after heart transplantation in children under six years of age.

BACKGROUND: Survival after heart transplant has improved and more attention is focused on developmental outcomes. We aimed to determine the survival, morbidity, and developmental outcomes of young children after heart transplant. METHODS: All children under 6 years of age having a heart transplant in Edmonton between 1999 and 2006 were included in this inception cohort study. Demographics, pretransplant, transplant, and posttransplant variables were collected. The association of potentially predictive variables with neurodevelopmental outcomes at least 12 months posttransplant were determined by univariate and multiple regression analyses. RESULTS: Thirty-three children had a heart transplant; 18 with congenital heart disease (CHD) and 15 with cardiomyopathy-myocarditis (non-CHD). Mortality during 19 (8) months of follow-up was 12% (95% confidence interval [CI] 3% to 28%). Survivors had frequent low weight (28%) and height (31%), and delay in language (41%), motor (52%), mental (34%), and general adaptive composite (48%) scores. Only CHD was associated with death-disability-mental delay on multiple regression (odds ratio 7.94; 95% CI 1.6 to 39.4, p=0.011). The CHD was also associated with mental and language delay on multiple regressions. Mental delay occurred in 8 (53%) with CHD and 2 (14%) with non-CHD (p=0.05). Mental score of 85 or greater was found in 13.4% of patients with CHD compared with 50% with non-CHD (p=0.05). CONCLUSIONS: In this single-center inception cohort study, adverse neurodevelopmental outcomes in survivors of heart transplant before the age 6 years were common, particularly in those with CHD. Careful pretransplant and posttransplant counseling are needed, and close follow-up with early intervention for these high-risk children is imperative.