NEUROPSYCHOLOGICAL FUNCTIONING IN CHILDREN WITH A … · Table of Contents i Table of contents Dankwoord iii Chapter 1 Introduction 1 1.1 General introduction 3 1.2 Neurocognitive

NEUROPSYCHOLOGICAL FUNCTIONING IN CHILDREN WITH A SURGICALLY CORRECTED CONGENITAL HEART DISEASE

Thesis submitted in fulfilment of the requirements for the Degree of Doctor in Medical Sciences 2007 Marijke Miatton Promotor: Prof. Dr. G. Vingerhoets Copromotor: Prof. Dr. D. De Wolf

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© 2007 Marijke Miatton, Ghent, BelgiumAlle rechten voorbehouden. Behoudens de uitdrukkelijk bij wet bepaalde uitzonderingen magniets uit deze uitgave worden verveelvoudigd, opgeslagen in een geautomatiseerd gegevens-bestand of openbaar gemaakt, op welke wijze dan ook, zonder de uitdrukkelijke voorafgaandeen schriftelijke toestemming van de uitgever.

Voor mama en papa “On ne voit bien qu’avec le coeur”

L e d e n e x a m e n c o m m i s s i e Prof. Dr. Guy Vingerhoets Prof. Dr. Daniël De Wolf Dr. Katrien François Prof. Dr. Evert Thiery Prof. Dr. Paul Boon Prof. Dr. Raymond Cluydts Prof. Dr. Dirk Matthys Prof. Dr. Ann Swillen Prof. Dr. Johan Vandewalle

Table of Contents i

T a b l e o f c o n t e n t s Dankwoord iii Chapter 1 Introduction 1

1.1 General introduction 3 1.2 Neurocognitive consequences of surgically

corrected congenital heart defects: a review 4 1.3 Goals and methodology 43

Chapter 2 Neuropsychological performance in school-aged children

with a surgically corrected congenital heart disease. 49 Chapter 3 Intellectual, neuropsychological and behavioral

functioning in children with tetralogy of Fallot. 65 Chapter 4 Medical and surgical predictors of neuropsychological

deficits in school-aged children with a surgically corrected congenital heart disease. 81

Chapter 5 Behavior and self-perception in children with a surgically

corrected congenital heart disease. 91 Chapter 6 Do parental ratings on cognition reflect

neuropsychological outcome in congenital heart disease? 111

ii Table of Contents

Chapter 7 General discussion 123 Chapter 8 Conclusion 133 References 135 Summary/ Samenvatting / Résumé 141 List of abbreviations 145 Appendix 147

Dankwoord iii

D a n k w o o r d Bij het uitvoeren van dit doctoraatsonderzoek heb ik kennis mogen maken met mensen die een waardevolle bijdrage leverden aan dit werk. Ik wil hen dan ook persoonlijk bedanken. Mijn promotor, Prof. Dr. Vingerhoets, beste Guy, bedankt voor alle kansen die ik kreeg. Ik heb niet alleen mogen proeven van wetenschappelijk onderzoek, maar ook van klinische dienstverlening, onderwijs en stagebegeleidingen. Zowel professioneel als persoonlijk heb ik er veel aan gehad. Mijn co-promotor, Prof. Dr. De Wolf, Daniël, bedankt voor de motiverende gesprekken en mijn verontschuldigingen voor het stalken! Bedankt ook om altijd zo oprecht geboeid te blijven door dit onderzoek. Dr. François, ik kon altijd rekenen op uw bereidwilligheid om te helpen. Ik heb veel opgestoken van uw correcties en suggesties. Bedankt! Prof. Dr. Thiery, bedankt voor de nauwgezette revisies van de manuscripten, maar tevens voor de leerrijke wekelijkse patiëntenbesprekingen en de vlotte samenwerking. Dankzij jullie is dit werk waardevoller geworden! Ook Prof. Boon verdient een dankwoord voor de kans om dit doctoraat tot een goed einde te brengen. Graag bedank ik ook de leden van de examencommissie en leescommissie. Bedankt Prof. Dr. H. Verhaaren, voor de aangename kennismaking met de werkgroep ‘Psychosocial care in CHD’, Dr. Mark Schittekatte en Dr. Eline Van Hoecke voor de hulp bij enkele methodologische aspecten, Christelle Maes van het secretariaat kindercardiologie voor het opzoeken van patiëntendossiers, Ilse Coomans voor de bemoedigende woorden omtrent statistiek, Chris Leyman voor de

iv Dankwoord

toffe gesprekken wanneer ik me door de stapel dossiers aan het werken was, Anneleen Nechelput voor het opzoeken van de genetische resultaten van de kinderen. Ook dank aan Chris Deloof, voorzitter van Hartekinderen v.z.w. voor de interesse in het onderzoek en zijn toffe medewerking. Een speciaal woordje van dank ook aan de 10-jarige Lies Fauconnier, die zo’n mooie tekening maakte voor de omslag van dit boekje. I would like to thank Mrs. Susannah Carver for her careful reading and correction of the manuscript. Uiteraard zou dit onderzoek niet tot stand gekomen zijn zonder de deelname van alle ouders en kinderen met een congenitale hartafwijking. Bedankt om tijd vrij te maken voor dit onderzoek! Bedankt ook aan de scholen en vooral aan het administratieve personeel dat ik soms tot vervelens toe contacteerde met mijn specifieke wensen, en aan alle gezonde kindjes die deelnamen. In het laboratorium voor neuropsychologie bedank ik met heel mijn hart Christiaan, niet alleen voor de administratieve ondersteuning, maar vooral voor de gemoedelijke sfeer die er heerst in het secretariaat. Ook de andere collega’s Celine, Katrien, Nathalie, Nele en Ruth bedank ik voor het samen delen van lief en leed! Samen naar de eindstreep hè Ruth! Dank ook aan alle studenten die de revue passeerden en schoorvoetend hun vragen kwamen stellen, om toch maar niet te veel te storen tijdens dit onderzoek. Op persoonlijk vlak vermeld ik graag Wendy krul! Je hoort het niet graag maar je bent iemand om naar op te kijken! Ik heb bewondering voor de manier waarop jij alle uitdagingen aangaat die je op je weg tegenkomt. Bovendien mag ik altijd op jou rekenen! Het samen lachen, onnozel doen en vooral de situaties waarin we samen terecht komen zijn bijzonder lachwekkend en daarom zo onbetaalbaar! Dank u Limburger-vriendinneke! Mijn superzus dank ik omdat we het zo goed hebben met mekaar! En omdat ik door jullie tot “apetrotse meter” werd bevorderd voor Baby Alexis. Zonder de liefste mama en papa van de wereld zou ik nooit zijn wie ik nu ben! Niets wat ik hier schrijf kan omvatten wat ik voel voor jullie. Ik draag deze thesis aan jullie op!! En natuurlijk hoor ook jij, Fre thuis in dit rijtje! Ik ga mijn uiterste best doen om ook rust en kalmte uit te stralen voor je als jij in stressmomenten terechtkomt … You rock my world!! IHVJ! Bedankt allemaal! Marijke

1 Introduction 1

1 I n t r o d u c t i o n

1.1 General introduction

1.2 Neurocognitive consequences of surgically corrected congenital heart defects: a review. Neuropsychology Review 2006; 16 (2): 65-85.

1.3 Goals and methodology

Neuropsychological Functioning in Children with a Surgically Corrected Congenital Heart Disease

2 1 Introduction


1 Introduction 3

1.1 General introduction

Congenital heart disease is defined as a gross structural abnormality of the heart or intrathoracic great vessels with actual or potential functional significance (Nuutinen et al, 1989). The incidence of congenital heart disease (CHD) in the Western industrialized world is estimated at 5 to 12 per 1000 live births (Hofman, 1995). For many of these children surgical treatment or catheterization is inevitable. Although innovation in medical and surgical management has resulted in a significant decrease in mortality over the past 30 years, morbidity remains a concern. Follow-up studies have identified developmental and neurological abnormalities in as many as 25% of survivors (Bellinger et al, 1999). Initially, studies attributed neurodevelopmental sequelae in children with CHD to surgical procedures, but it soon became clear that the etiology had to be multifactorial with preoperative, peri-operative and postoperative factors all contributing to outcome. The article “Neurocognitive consequences of surgically corrected congenital heart defects: a review” (1.2) summarizes the existing literature on neuropsychological sequelae in children with CHD as well as possible predictors for adverse outcome. The goals of this thesis and the methodology will be discussed in 1.3.


4 1 Introduction

1.2 Neurocognitive consequences of surgically corrected congenital heart defects: a review

A b s tr ac t

With advances in surgical procedures, neuropsychological assessment after congenital heart defects (CHD) and pre, peri- and /or postoperative predictors of adverse outcome, became an important focus in research. We aimed to summarize neuropsychological sequelae associated with different types of CHD, to critically review the methodology used in more than 20 empirical studies that were retrieved from biomedical electronic search engines, and to identify possible directions for future research. Despite the lack of adequate control groups and long-term studies, there seem to be some cognitive deficits. The largest group of children with isolated congenital heart defects present with normal intellectual capacities. However, they tend to show language deficits and motor dysfunction. Although performances on memory tasks are good, unambiguous conclusions concerning their attentional and executive functioning are still lacking. Serious behavioral problems are not an issue. In addition to a detailed description of the (neuro) psychological consequences of pediatric cardiac surgery, an overview of the predictors of the cognitive defects is provided. I n t r o d uc t i o n

Congenital heart disease (CHD) is described as a gross structural abnormality of the heart or intrathoracic great vessels with actual or potential functional significance (Nuutinen et al., 1989). The incidence of CHD has been thoroughly studied (Hofmann & Kaplan, 2002). A great variety in incidence exists, caused by the definition of CHD used, time of diagnosis, and diagnostic tools. World wide, the incidence of moderate to severe CHD is estimated to be about six per 1000 live births. This incidence increases to 75 per 1000 when tiny ventricle septal defects (VSD) present at birth and other trivial lesions are included. Congenital Heart Defects can be graded into three groups. The first group is severe CHD, which includes most of the patients who present severely ill in the newborn period or early infancy and who will need expert cardiologic care and (multiple) surgical interventions. Defects as Transposition of the Great Arteries (TGA), Tetralogy of Fallot (TGA), Hypoplastic Left Heart Syndrome (HLHS), and large Ventricle Septal Defect (VSD) can be found in this group and account for 2.5 to 3 per 1000 live births. Moderate CHD forms a second group, which needs expert care, but less intensive than those mentioned in the first group. The number of operations can often be minimized, and sometimes reduced to interventional catheterization. The incidence of these moderate CHDs, as mild or moderate Aortic


1 Introduction 5

Stenosis (AS), Pulmonary Stenosis (PS), or large Atrial Septal Defects (ASD), is estimated at three per 1000 live births. The most numerous group consists of patients that are most often asymptomatic, and often undergo early spontaneous resolution of their lesion. Small VSD, small ASD, small Patent Ductus Arteriosus (PDA) and mild Pulmonary Stenosis (PS) are part of this group (Hoffmann & Kaplan, 2002). Obviously, this description is not complete; we chose to mention those defects discussed in the review later. Since a thorough description of the pathology of CHD and the corresponding (surgical) treatment, were not within the scope of this review, we refer the interested reader to May, 2001.

Table 1. Degrees of CHD, cardiac pathology and common treatment *

CHD Cardiac pathology Common treatment SEVERE CHD Transposition of the Great Arteries (TGA)

Connection between ventricles and great arteries is inversed

First: keeping ductus arteriosus open through prostaglandins + opening the atrial septum (Rashkind procedure) Next: Arterial Switch Operation

Tetralogy of Fallot (TOF)

Ventricle Septum Defect+ overriding aorta+ pulmonic stenosis

< 3 months: shunt or balloon dilatation of the pulmonic valve > 3 months: total surgical correction

Large Ventricular Septal Defect (VSD)

A communication in the ventricular septum

Surgery: the VSD is surgically patched with synthetic material

Hypoplastic Left Heart Syndrome (HLHS)

The left ventricle is maldeveloped, its size and functional ability is insufficient to sustain life. The mitral valve, aortic valve and first portion of the ascending aorta are small

Heart transplantation or 3 staged operation: 1. Norwood procedure 2. Glenn or hemi-Fontan

procedure 3. Fontan procedure

MODERATE CHD Atrial Septal Defect (ASD)

A communication in the atrial septal wall

Surgical closure or closure through interventional catheterization

Pulmonary Stenosis (PS)

The pulmonary valve is thickened and does not open completely

Balloon dilatation

Aortic Stenosis (AS) The aortic valve does not open In the neonate: balloon dilatation


6 1 Introduction

CHD Cardiac pathology Common treatment completely due to thickening and commissural fusion

or surgical valvotomy In children: usually asymptomatic, first balloon dilatation, later: replacement of the valve with a human valve (homograft), its own pulmonary valve, or with a mechanical valve

MILD CHD Patent Ductus Arteriosus (PDA)

The ductus arteriosus (blood vessel closes soon after birth situated between the aorta and pulmonary artery) does not close spontaneously

Closure of the vessel through catheterization

Small VSD Sometimes asymptomatic

Small ASD Sometimes spontaneous closure

Mild PS Sometimes asymptomatic

* Obviously, this table is not complete; we chose to address only those congenital cardiac defects, mentioned in the review.

In Western countries, an incidence of 0.3 to 1% has been noted for children with CHD who require surgical treatment (Van Hoecke & Dhont, 2004). Due to medical and technical improvements, the surgical morbidity of infants has dramatically declined over the years. Although a normal life expectancy and quality of life might be assumed in patients with early normalization of their cardiopulmonary status, negative developmental outcome might not supervene until later in life. Indeed, follow-up studies have identified developmental and neurological abnormalities in as many as 25% of survivors (Bellinger et al., 1999). Early identification of these developmental deficits and subsequent remedial interventions are of paramount importance to guarantee an optimal development in these children. In contrast with neuropsychological evaluation following cardiac surgery in adults, investigation of the neurocognitive and behavioral deficits following congenital heart disease was not triggered by subjective complaints of either the parents or the children. Instead, improvements in surgical techniques made cardiologists wonder whether this would be reflected in improved neurocognitive outcome. It is expected that having a severe CHD, requiring (multiple) surgical intervention(s) will have more impact on neuropsychological functioning, than a mild CHD. In this review, we describe the global cognitive functioning and psychosocial behavior of children with surgically corrected CHD, in addition, we offer a short


1 Introduction 7

overview of the medical and surgical parameters that can predict developmental disabilities after open-heart surgery, in order to identify possible directions for future research. S e ar c h m e th o d

The Web of Science or Medline search engines identified studies published from 1950 until 2004. Following terms or combinations of these terms were used: congenital heart disease, child or children, neuropsychology, cognition, cognitive functioning, and neurodevelopment. The term ‘congenital heart disease’ revealed 8481 articles on the Web of Science and 9111 on Medline. In combination with ‘child’ or ‘children’ Web of science identified 2860 articles. The search with the terms ‘congenital heart disease’ and ‘cognition’ revealed 57 articles on the Web of Science, and 40 on Medline. Combining ‘congenital heart disease’ with ‘neuropsychology’ revealed 14 articles on Web of Science and 12 on Medline. Finally, ‘congenital heart disease and neurodevelopment’ resulted in 7 articles on the Web of Science and in 33 articles on Medline. Additional references were retrieved from selected articles. The premised selection criteria for the articles were: (1) the abstract had to make clear that developmental deficits in children with CHD were studied by means of intellectual performances or by means of developmental neuropsychological assessment batteries or (2) the study was designed to study medical and/or surgical predictors of the found developmental shortcomings. In total, 57 studies were included, of which 23 were intensively reviewed. Because of methodological reasons such as not using an assessment battery to rate “neurodevelopment” but only a neurological opinion, or using adolescents instead of children, 38 studies were excluded. Studies on specific neuropsychological domains were only available from 1991 onwards. Table 2 lists an overview of studies on cognitive functioning from 1991 until today. Most of the pediatric studies mentioned in this review, sought to define the range of neurodevelopmental dysfunctions that parents and primary care providers can expect after surgery. C o g n i ti v e an d ps yc h os oc i al be h a v i o r a l f u n c ti on i n g

I n t e l l e c t u a l p e r f o r m a n ce

Initially, investigators focused on the intellectual consequences of pediatric cardiac surgery. The median full scale IQ of children with Hypoplastic Left Heart Syndrome (HLHS) who underwent at least two stages of surgical palliation was found to be 88, implying a low average intelligence (Kern et al., 1998). When standardized testing was performed in 28 children with HLHS who had undergone palliative surgery


8 1 Introduction

(mean age at testing 8.6 years), the results revealed lower performance IQ scores than verbal IQ scores, borderline low range scores for full scale IQ in 35.7% of the survivors and, in 17.8% IQ scores below 70 were reported (Sharma et al., 2000). A first study on 38 children with various CHDs who were assessed 22 months to 6 years after open-heart surgery, reported normal intellectual capacities (Dickinson & Sambrooks, 1979). It became overall accepted that undergoing cardiac surgery did not impair intellectual function (Haneda et al., 1996). Comparative studies on pre- and postoperative developmental and cognitive functioning in three groups of children (CHD, children awaiting bone marrow transplantation, and healthy children) revealed, both before and after surgery, IQ-scores within the normal range. Both the cardiac and bone marrow transplant group however, had significantly lower IQ-scores compared to the healthy group (Wray & Sensky, 1999). Most researchers conclude that IQ-scores of the larger part of children with CHD are within the normal range, although several studies report lower IQ scores in some specific groups with more severe cardiac pathology. S c h o o l a c h i e v e m e n t

School performance was the next object of study. Children with transposition of the great arteries (TGA) showed overall lower scores on arithmetic, learning, and general knowledge tests. Of 60 children with TGA operated as neonates, 23.3% performed worse than expected on the age of 7 years. In this lower performance group, 18.3% performed lower than one standard deviation (SD) and 5% performed lower than two SD of the mean score (Hövels-Gürich et al., 2002). Children with cyanotic defects in general appear to have lower abilities for arithmetic, reading, and spelling. Lower than expected values on reading and math are also found in children with HLHS of which one third receives special education (Mahle et al., 2000). Although most children with a CHD seem to perform well at school, about 20% is considered to perform below average. Later research isolated specific neurocognitive domains in order to define the contribution of a specific cognitive dysfunction to this underachievement. A t t e n t i o n

Only a few studies specifically included attentional tasks in their neuropsychological protocol. Children with TGA, Tetralogy of Fallot (TOF), or VSD were investigated 9 to 10 years after corrective surgery, and their performances on attentional tasks were compared to those of healthy children. No significant differences between the performances of both groups were found on the Stroop Color Word Test and the Trail Making Test (Oates et al., 1995 a). Another study that included attentional measures compared children with a secundum atrial septal defect (ASD) that was either surgically closed or by using a transcatheter device (Visconti et al., 1999).


1 Introduction 9

These researchers concluded that the device group made more errors of commission suggesting impulsivity. The scores on the attentiveness index were also lower. The initial aim of this study however was the comparison of the two treatment approaches mentioned, and not the investigation of attentional problems in se. Overall, the findings concerning attentional measures appear too fragmented and contradictory to allow for a viable interpretation. M e m o r y

In 1994, a study on 29 children with TGA, aged 7 to 12 years was reported. The children with TGA were compared to 36 children that suffered from an innocent cardiac murmur that did not require treatment or a small VSD closing spontaneously. The children performed a number of neuropsychological tests including the Rey Auditory Verbal Learning Test and the Rey-Osterrieth Complex Figure Test. The children with TGA did not display any problems on these tasks and their performances were rated equal to those of the control group (Wright & Nolan, 1994). Confirmation of these findings was offered by other studies on children with TGA or TOF. Compared to children with VSD and healthy schoolchildren, the heart group showed no differences on the Rey-Osterrieth Complex Figure Test and the Selective Reminding test (Oates et al., 1995 a). Up to 96.7% of the children who had an arterial switch operation for TGA performed normally on learning and memory tasks (Hövels-Gürich et al., 2001). The single ventricle group however displayed significantly lower scores for design memory at the age of 5 years (Forbess et al., 2002). Generally, studies on memory functioning revealed that children with TGA or TOF reach performances within the average range. L a n g u a g e

Studies investigating the expressive language development of children aged 16 to 30 months with a TGA in combination with a VSD, report a delay of two to four months in communicative development (Bellinger et al., 1997). Lower than expected scores on language tests were also found in survivors of staged palliation for HLHS (Sharma et al., 2000). Similarly, language deficits were observed in children with TGA: 18.3% had reduced scores on expressive language tasks (all below 1 SD), 21.6% on receptive language tasks (18.3% below 1 SD, 3.3% below 2 SD) (Hövels-Gürich et al., 2002). We conclude that most studies investigating language skills report substantial problems on a variety of tasks. P s y c h o m o t o r f u n c t i o n s

In early research on neuropsychological deficits, reduced gross motor coordination in children with cyanotic heart diseases was frequently reported (Limperopoulos et


10 1 Introduction

al., 1999) and has been supported by most research to date (Wright & Nolan, 1994; Oates et al., 1995 a). Also fine motor dysfunctions occur in about 22.1% of children with TGA (Hövels-Gürich et al., 1997, Hövels-Gürich et al. 2002). Survivors of an operation for HLHS tend to have weaker visual motor integration capabilities (Uzark et al., 1998). Studying children with various CHDs before and after cardiac surgery revealed poorer locomotor skills both before and after the operation (Wray & Sensky, 1999). Gross and fine motor deficits are estimated to appear in 42% of the children (Limperopoulos et al., 2002). Clearly, a large percentage of children with CHD display motor deficits. P s y c h o s o c i a l b e h a vi o r

Both behavior at home, measured by the Child Behavior Checklist and behavior at school, measured by the Teacher Report Form have been object of study. Early reports on behavior in children with TGA aged 7 to 12 years, rated by parents and teachers, revealed no significant differences compared to healthy children (Wright & Nolan, 1994; Aldèn et al., 1998). Moreover, parents of children with a TGA perceived significantly fewer behavioral problems than expected from normative data (Bellinger et al., 1997). The behavior of school-aged survivors of staged palliation for HLHS was also investigated and showed 50% to fall within the normal range. In 17.8% however, criteria for borderline significant or clinically significant behavioral problems on two or more subtests were met (Sharma et al., 2000). Children with a secundum ASD display higher prevalence of problem behavior according to their parents, particularly the behavior classified as “internalizing” (Visconti et al., 1999). The findings on psychosocial behavior depend on the type of cardiac defect and do not permit accurate conclusions for the whole group of children with CHD. S u m m a r y

Although the IQ scores of the larger part of children with CHD fall within the normal range, several studies report lower IQ scores in some specific groups with more severe cardiac pathology. On memory tasks, children with TGA or TOF reach performances within the average range. Reduced performance in school has been noted in some specific patient groups. Concerning language, delays of two to four months in communicative development in children with TGA in combination with VSD have been reported, which is supported by other studies showing language deficits. Studies on motor functions conclude that most of the children with CHD display gross and fine motor deficits. The lack of studies on attentional and executive tasks do not allow for a viable interpretation. Early reports on psychosocial behavior in children with TGA showed no significant differences with


1 Introduction 11

healthy children, although these studies are very diverse and do not permit accurate conclusions. Despite the high incidence of CHD, psychological and neuropsychological research in this population remains scarce. The difficult medical circumstances and methodological constraints for research in this population play an important part in this scarcity. The acute critical status of the newborn often requires immediate medical intervention, reducing the importance of a neurodevelopmental testing at that stage. Further, the functional testing that can be completed on neonates is extremely limited and the illness of the child reduces the predictive validity of a preoperative functional assessment. Because of these limitations in preoperative assessment, research focus shifted to quantifying the impact of the medical and surgical variables on neuropsychological functioning, in order to cause refinement of the medical policy and/or surgical techniques. In the next paragraph, these predictors will be summarized. M e d i c a l a n d s u r g i c a l p r e d i c t o r s o f d e v e l o p m e n t a l d i s a b i l i t i e s a f t e r o p e n - h e a r t s u r g e r y

As mentioned before, the critical status of the newborn with a CHD often requires immediate intervention. After the inventory of developmental disabilities, research focus shifted to etiology. Initially, studies attributed neurodevelopment sequelae in children with CHD to surgical procedures but it soon became clear that the etiology had to be multifactorial. Preoperative, intraoperative, and postoperative factors all contribute to the outcome. Preoperative factors include the prevalence of neurobehavioral abnormalities before surgery (Limperopoulos et al., 1999), age at operation, and severity of the disease. During the operation, different cardiopulmonary bypass techniques such as continuous low-flow bypass or circulatory arrest are used, depending on the type of cardiac defect. These techniques demand several alterations in homeostasis: anesthesia, cooling and rewarming, reduction in pump flow or circulatory arrest, pH management, oxygenation by membrane oxygenator, hematocrit of the prime and changes in blood gases (Kirkham, 1998). Finally, important postoperative factors such as hemodynamic stability after the operation, length of stay in the intensive care unit, and the possible need for multiple operations are mentioned. P r e o p e r a t i v e f a c t o r s

P r e v a l e n c e o f n e u r o b e h a v i o r a l a b n o r m a l i t i e s b e f o r e s u r g e r y

Preoperative neurobehavioral assessments and neurological examination in newborns with congenital heart defects revealed abnormalities in more than half of the cohort. These abnormalities included hypotonia, hypertonia, jitteriness, motor asymmetries, absent suck and poorly modulated behavioral state organization


12 1 Introduction

profiles (to make smooth and organized transitions between states e.g. sleep to arousal, to alert, to crying). Feeding difficulties were also common, as well as seizures and micro- or macrocephaly. In the genesis of brain injury in these children, prevalence of neurobehavioral abnormalities before surgery is underappreciated and should be brought under attention (Limperopoulos et al., 1999). Preoperative neuropsychological functioning, however, is very difficult to assess. Some forms of critical congenital heart disease must be repaired hours to weeks after birth, and the functional testing that can be completed on even healthy full term neonates is severely limited in terms of scope and predictive validity for later outcomes. G e n e t i c s

Few studies report the genetic screening of the children included, although it is known that 5 to 8 % of CHDs result from chromosome abnormalities, more specifically Down syndrome and 22q11.2 deletions. Since approximately 15 to 20% of all conotruncal cardiac malformations will have the 22q11.2 deletion, this genetic syndrome is one of the most common etiologies of heart defects in cardiology (Colemann, 2002). Because these genetic syndromes involve intellectual and neuropsychological deficits as well, they are crucial in the study of causative factors. Management strategies during the operation have been intensively examined and have been implicated as predictive factors of adverse postoperative neurodevelopmental dysfunction. The great interindividual variation in developmental outcome however, suggests that patient-specific factors may play an important role. Polymorphisms of apolipoprotein E have been named as a risk factor for worse neurological outcome after central nervous system injury. When determining the APOE genotype of children with CHD operated on age 6 months or less, results show a significant effect of the APOE є2 allele to predict lower psychomotor developmental index at 1 year of age after cardiac surgery. This finding is independent of race, socioeconomic status, cardiac defect, and use of deep hypothermic cardiac arrest. The study found no evidence for an APOE є4 effect on neurodevelopmental outcome. This APOE genotype-environment interaction demonstrates that genetic polymorphisms may explain some of the interindividual variation in developmental outcome after surgery for CHD. Broader neurodevelopmental evaluation of these children at an older age will clarify the impact of the APOE genotype on long-term outcome (Gaynor et al., 2003). P r e m a t u r i t y

No exact incidence of low birth weight or prematurity within the group of children with CHD is reported. Studies on neurodevelopmental outcome after surgery for CHD only sporadically mention low birth weight (< 2500g) and low gestational age (<32 weeks) as exclusion criteria. Prematurity and low birth weight are often


1 Introduction 13

associated with cognitive deficits, so they should be used as exclusion criteria or they should be entered in the study as a possible confounding variable. B r a i n i n j u r y

On preoperative magnetic resonance imaging, five of 15 children with either cyanotic heart disease or congestive heart failure showed brain abnormalities. All lesions (ventriculomegaly and cerebral atrophy) were subclinical (McConnell et al., 1990). Hemodynamic disturbances, caused by low cardiac output for instance, might also be associated with poor brain growth, embolic infarction, cerebrovascular thrombosis, and abscess formation (Miller & Vogel, 1999). In 2002, an MRI study was conducted before and after congenital heart surgery. Preoperative examinations revealed periventricular leukomalacia in 16% of the patients and infarct was present in 2%. Postoperatively, new lesions or worsening of preoperative lesions were found in 67% of the subjects (Mahle et al., 2002). S e v e r i t y o f t h e d i s e a s e

Differences in severity of various congenital heart defects are difficult to rate because of the subjectivity in diagnostic parameters. Several propositions to quantify the degree of heart failure have been made. In 2001, the New York University Pediatric Heart Failure Index (NYU PHFI), derived from signs and symptoms, medical regimen, and ventricular physiology, was evaluated and appeared to be a reliable instrument for the evaluation of heart failure severity in children (Connolly et al., 2001). A second measure, the New York Heart Association Class classifies the functional status of the child. Initially, the classification only existed for adults, yet in 2001, a modification was made for the use in children (Bruns et al., 2001). During the conduction of the studies in this review, these measures did not exist. Therefore, other distinctions, for instance between acyanotic and cyanotic congenital heart defects, emerged. Many researchers tried to find differences in neurocognitive functioning between these two groups of congenital heart defects. Several studies in the 1960s (Linde et al., 1967; Rosenthal, 1967; Rasof et al., 1967; Feldt et al., 1969; Silbert et al., 1969) found children with cyanotic congenital heart diseases to have lower IQ scores and to show inferior performance in gross motor skills, perceptual motor skills, and visual reaction time than children with acyanotic congenital heart defects. Other studies could not confirm this hypothesis (Wray & Sensky, 1999). A second distinction frequently made, is between univentricular and biventricular congenital heart defects. Overall, researchers agree that children with HLHS (a univentricular group) perform worse on cognitive outcome than do children with other congenital cardiac defects (Miller et al., 1996; Sharma et al., 2000; Forbess et al., 2002; Uzark et al., 1998). Unfortunately, these distinctions are no standardized measures and depending on the definitions used by the researcher, different classifications can emerge, making generalizations of study results unreliable. To


14 1 Introduction

achieve homogeneity in the study groups, the use of validated and reliable indices for the severity of heart failure (NYU PHFI) or the functional status of children with CHD (in the New York Heart Association Class) will become indispensable in future research. A g e a t r e p a i r

The unstable cardiac status of the newborn often requires urgent treatment. Certain heart defects however, are repaired later in life, prolonging the hypoxic status. A significant negative correlation between age of corrective surgery (for cyanotic heart defects) and IQ scores has been proven, suggesting that longer periods of chronic hypoxia may reduce intelligence (O’Dougherty, 1983; O’Dougherty, 1985). Another advantage of surgery on neonates is the lower incidence of postoperative seizures in neonates than in older infants (Newburger et al., 1993). The results of this kind of studies have led surgeons to operate on the neonates as soon as possible. However, contrasting evidence stated that for children with TGA or TOF delaying the operation does not appear to adversely affect their intellectual development (Oates et al., 1995 a).


1 Introduction 15

I n t r a o p e r a t i v e f a c t o r s

Results on the relation between bypass techniques and neurological problems (Colemann, 2002), or brain injury (Scallan, 2003) have been reviewed elsewhere. We will give an overview of some techniques that have been investigated in relation to neuropsychological consequences. D e e p h y p o t h e r m i c c i r c u l a t o r y a r r e s t v e r s u s c o n t i n u o u s l o w - f l o w

c a r d i o p u l m o n a r y b y p a s s

With the introduction of circulatory arrest (CA) at deep hypothermia, it became possible for the surgeon to work on a field free of catheters and blood. In 1953, the successful closure of an atrial septal defect (ASD) in a 5-year-old child with the use of surface cooling followed by cessation of circulation for 5 minutes 30 seconds was reported (Lewis & Taufic, 1953). Later the principle was extended by reducing the brain’s temperature to 20°C or lower to permit extended periods of CA. Animal studies, that did not find obvious signs of cerebral damage, formed the basis for the view that up to 60 minutes of CA at 20°C is safe. In later research on hamsters the “safe” period for CA was limited to 30 minutes with a maximum of 45 minutes (Treasure et al., 1983). Finally, it was stated that the ‘true’ safe period might be as short as 20 minutes at 18° C (Scallan, 2003). However, evidence that the degree of increase in levels of creatine kinase isoenzyme BB, a specific marker for ischemia, is directly related to duration of arrest time in the presence of hypothermia, has raised concern about the safety of CA (Rossi et al., 1986; Ekroth et al., 1989; Rossi et al., 1989). Its use has also raised concerns because of the vagueness of the effects on the cerebral functioning and the neurological and developmental status. The association between cardiopulmonary bypass perfusion variables and later cognitive function has often been examined (Bellinger et al., 1999; Wright & Nolan, 1994; Newburger et al., 1993). A cohort of children who had undergone CA was compared to their siblings and to a group of children that had undergone corrective surgery with moderate hypothermia and continuous cardiopulmonary bypass. The CA group had significantly lower IQ-scores than the siblings and the moderate hypothermia group. Per minute of circulatory arrest time a reduction of 0.53 IQ- points was noted (Wells et al., 1983). No association between the duration of deep hypothermic CA and cognitive performances was found, but results suggest that for core cooling periods of less than 20 minutes’ duration, shorter cooling periods were associated with lower scores. These data suggested that patients undergoing relatively long periods of deep hypothermic CA might require some minimum time of cardiopulmonary bypass cooling to avoid central nervous system injury (Bellinger et al., 1991). Intelligence has been shown to be weakly but significantly inversely related to the duration of bypass. In addition, intelligence tended to be inversely related to the duration of circulatory arrest, but not to core cooling time on bypass or


16 1 Introduction

degree of hypothermia. Combined CA and low flow bypass in the neonatal arterial switch operation is associated with neurological as well as fine and gross motor impairment but appears to be well tolerated concerning cognitive functions as based on a formal intelligence testing (Hövels-Gürich et al., 1997). The perioperative neurological effects of hypothermic CA versus low-flow cardiopulmonary bypass in infant heart surgery were thoroughly investigated (Newburger et al., 1993). The use of CA was associated with greater central nervous system perturbation in the early postoperative period than a strategy consisting predominantly of low-flow cardiopulmonary bypass. The latter has recently even been called superior to CA because it does not impair cerebral perfusion (Scallan, 2003). This finding was not confirmed by a study on the association between the children’s functioning at age 7 to 12 years and medical and surgical parameters. No statistically significant association between the IQ scores, achievement tests and surgical variables could be noted. Periods of hypothermia longer than 45 minutes were strongly associated with an IQ of less than 85 and later neurological abnormality, suggesting that the use of CA or low-flow bypass was not as important as the duration of hypothermia (Miller et al., 1996). A study on the effect of CA as a support technique in 158 children with TGA at 4 years of age, revealed an association between assignment to CA and a reduced ability to imitate oral movements and speech sounds, a greater severity of abnormalities of volitional oral movements, more articulation errors, decreased performances on polysyballic repetitions, and more prevalent apraxia of speech (Bellinger et al., 1999). p H m a n a g e m e n t d u r i n g c o r e c o o l i n g : a l p h a v e r s u s p h - s t a t m e t h o d

During cardiopulmonary bypass, pH and blood gases are frequently measured. There has been long controversy about whether the results should be reported at the temperature at which they are taken or corrected to the value at a temperature of 37° C. For the former, to maintain a normal pH, carbon dioxide is added to the bypass circuit (pH-stat strategy), whereas for the latter the pH is allowed to become progressively alkaline (α-stat strategy) (Kirkham, 1998). Studies on the developmental and neurological effects of pH management for deep hypothermic cardiopulmonary bypass have proven children randomized to the pH-stat and α- stat method not to differ significantly at 1 year of age in their scores on the Bayley Infant Scales of Development or in their neurological examination. In addition, at the age of 2 to 4 years both groups of children had similar development as assessed by parental responses (Bellinger et al., 2001). H e m o d i l u t i o n

In the 1950s, hemodilution during cardiopulmonary bypass was introduced to decrease homologous blood use and was thought to improve microcirculatory flow. However, magnetic resonance and near-infrared spectroscopy suggest that, in animal


1 Introduction 17

models, currently recommended protocols for hemodilution during cardiopulmonary bypass might cause brain injury by hypoxic-ischemic injury. Further, hemodilution might reduce perfusion pressure, increases cerebral blood flow and reduces the oxygen carrying capacity of the blood, which increases the risk of adverse neurological outcome. This hypothesis was tested by randomly assigning children needing reparative cardiac surgery at less than 9 months of age to undergo hemodilution to a hematocrit level of approximately 20% versus 30%. At age of 1 year the children underwent a neurological examination and developmental evaluation. Results showed that the children assigned to the lower-hematocrit group had worse perioperative outcome and a lower psychomotor developmental index (PDI). A significantly greater proportion of these children showed PDI scores of more than two standard deviations less than the population mean. Deficits were mostly found in motor function but other domains, for instance language or visual-motor integration that cannot be easily assessed in 1-year olds, might equally be affected. Future research needs to refine the optimum hematocrit level during infant cardiac surgery (Jonas et al., 2003). O x y g e n a t o r s a n d f i l t e r s

Data from adult research suggest that micro emboli, mainly bubbles and small particulate matter, occur during cardiopulmonary bypass and lodge in retinal and cerebral microcirculation, in association with poor neuropsychological outcome. The effect of the use of membrane oxygenators and line filters on neuropsychological outcome however remains controversial. The neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation (ECMO) after cardiac surgery show normal neuromotor outcome in 75% of the survivors and 50 % had a normal cognitive outcome (Hamrick et al., 2003).


18 1 Introduction

P o s t o p e r a t i ve f a c t o r s

N u m b e r o f o p e r a t i o n s

Logically, the risk for neuropsychological consequences increases after successive operations. For many children with complex congenital heart defects (for example HLHS) the Fontan procedure has become the definitive surgical treatment. These children usually undergo more than one cardiac surgical procedure. It has been shown that children, who had deep hypothermic circulatory arrest during an operation before the operation under study, had somewhat lower IQ-scores than expected. It was however not within the scope of this study to isolate the effect of additional palliative procedures on intellectual performance (Uzark et al., 1998). L e n g t h o f s t a y i n C a r d i a c I n t e n s i v e C a r e U n i t

The postoperative healing process of the child is reflected in the length of stay in the cardiac intensive care unit (CICU). Postoperative length of stay is a marker for various events as hypotension or hypoxia, which can culminate in adverse cognitive outcome. Longer postoperative stay in CICU was indeed associated with worse cognitive functioning in 8-year old children (Newburger, 2003).

C l i n i c a l a n d E E G - s e i z u r e s

Early transient postoperative clinical seizures are reported in 4 to 10% of infants with critical CHD who need open heart surgery. By the use of postoperative continuous EEG-monitoring, an even higher incidence of children with seizure activity is detected. Postoperative clinical and EEG seizures are associated with worse neurodevelopmental outcomes at ages 1 year and 2.5 years in children with TGA (Rappaport et al., 1998). The predictive value of the measures used at these ages is limited, yet the presence of clinical and EEG-seizures should not be underestimated. A g e a t t e s t i n g

Age at the moment of testing can play an important role in studying neurodevelopment in children with CHD. Differences in cognitive functioning between the acyanotic group and the cyanotic group have been reported, with the latter performing worse. Remarkably, this difference only presented in older children, suggesting that in the cyanotic group, impairment of cognitive functioning increases with age (Wray & Sensky, 2001). S u m m a r y

Initially, most studies attributed neurodevelopmental sequelae in children with CHD to surgical procedures but it soon became clear that the etiology is multifactorial


1 Introduction 19

with preoperative, intraoperative and postoperative factors all contributing to the outcome. The preoperative status of the child is the first step under consideration. Presence of neurobehavioral and brain abnormalities as well as prematurity should be investigated, including a genetic screening and determining the APOE -genotype. Further, studies should strive for homogeneity in the severity of CHD in the study groups by using validated and reliable indices for the severity of heart failure (NYU PHFI) or the functional status of children with CHD (in the New York Heart Association Class). The effects of cardiopulmonary bypass and circulatory arrest, pH management, hemodilution, oxygenators and filters can not be denied in this population nor can the severity of the disease, the need for multiple operations, length of stay in CICU and clinical and EEG seizures. Medical and surgical variables have been highlighted separately in this part of the review, but obviously the nature of CHD is too diverse and complex to relate neurodevelopmental disabilities to isolated parameters. D i s c u s s i o n a n d c on c l u s i o n s

In studies on children with CHD the great variety in both heart defects under study and test material used to assess neuropsychological performance is striking. This obviously complicates generalization of the results. Because of this existing variety in heart defects and the different treatment procedures they require, investigators preferentially studied one heart defect, often resulting in small sample sizes. In addition, most studies reflect an underestimation of the neurodevelopmental problems in children with CHD since investigators exclude children with serious neurological injury. To date, most studies were retrospective caused by difficult preoperative clinical circumstances and the methodological constraints of psychological and neuropsychological research in this population. Specific critical congenital heart diseases demand urgent repair and the functional testing that can be completed on neonates is extremely limited. Moreover, these children are acutely ill before surgery, reducing the validity of a preoperative functional assessment. The predictive value of these early assessments for later cognitive outcomes is therefore limited. Selecting an appropriate control group is also a methodological challenge in this group. Including healthy children as a control group is methodologically incorrect because neither physical, nor environmental aspects are equivalent in these groups. In children with CHD, developmental shortcomings can be attributed to several factors as for instance the surgical intervention or the emotional trauma of hospitalization. However, healthy children did not experience these causative factors in any way. To solve this problem, one can include children that underwent a non-cardiac surgical intervention but non-cardiac diagnoses do not hold the same


20 1 Introduction

potential risks of central nervous system damage, as do CHDs. Another option is to compare children with CHD that require open-heart surgery, to children with CHD that require closed surgical procedures (Haneda et al., 1996). However, in this case, differences in disease severity and surgical invasiveness may constitute another confound when comparing both CHD groups. Further, the need for follow-up studies increases. Inventories of preoperative neurological and genetic deficits and possible preoperatively present structural brain lesions will become essential. Follow-up studies will also clarify the persistence of developmental abnormalities. In future research, preoperative, intraoperative, and postoperative factors should be included when studying causes of neurodevelopmental disabilities. The cognitive domains of attention and executive functioning remain largely under investigated. As mentioned before, research on the developmental sequelae of CHD has been directed by the medical team, and not so much by subjective complaints on neurocognitive functioning by parents or children. As studies pointed out, a substantial part of children with CHD performs within average range, yet another group does display mild to moderate cognitive dysfunction. Examination of the subjective complaints of parents and children as well as competence perception of the children with CHD should be included in future research. Studies should strive for homogeneity in the severity of CHD in the study groups by using validated and reliable indices for the severity of heart failure (NYU PHFI) and the functional status of children with CHD (in the New York Heart Association Class). Only then can we draw firm conclusion on the different CHDs and their respective neurodevelopmental sequelae. Recognition of the population at risk will lead to prevention of serious sequelae. This review emphasized the existence of neurocognitive sequelae of CHD and highlighted the influence of medical and surgical parameters. Future research should continue to define the relationship between congenital heart disease and neurodevelopmental outcome, and to clarify the exact impact of surgical techniques on the long-term neuropsychological functioning. Providing modifications in cardiac and surgical management that will improve neurological and neurodevelopmental outcome in children with CHD is the overall aim of this research.


1 Introduction 21

R e f e r e n c e s

1. Aldèn, B., Gilljam, T., & Gillberg, C. (1998). Long-term psychological outcome of children after surgery for transposition of the great arteries. Acta Paediatrica , 87: 405-410.

2. Bellinger, D.C., Rappaport, L.A., Wypij, D., Wernovsky, G., & Newburger, J.W. (1997). Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries. Journal of Developmental and Behavioral Pediatrics, 18 (2): 75-83.

3. Bellinger, D.C., Wernovsky, G., Rappaport, L.A., Mayer, J.E., Castaneda, A.R., Farrell, D.M., Wessel, D.L., Lang, P., Hickey, P.R., Jonas, R.A., & Newburger, J.W. (1991). Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics, 87 (5): 701-707.

4. Bellinger, D.C.,Wypij, D., du Plessis, A.J., Rappaport, L.A., Riviello, J., Jonas, R.J., & Newburger, J.W. (2001). Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. Journal of Thoracic and Cardiovascular Surgery, 121 (2): 374-383.

5. Bellinger, D.C., Wypij, D., Kuban, K.C.K., Rappaport, L.A., Hickey, P.R., Wernovsky, G., Jonas, R.A., & Newburger, J.W. (1999). Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation, 100 (5): 526-532.

6. Bruns, L.A., Chrisant, M.K., Lamour, J.M., Shaddy, R.E., Pahl, E., Blume, E.D., Hallowell, S., Addonizio, L.J., & Canter, C.E. (2001). Carvedilol as therapy in pediatric heart failure: An initial multicenter experience. Journal of Pediatrics, 138 (4): 505-511.

7. Colemann, K. (2002). Genetic counseling in congenital heart disease. Critical Care Nursing Quarterly, 25 (3): 8-16.

8. Connolly, D., Rutkowski, M., Auslender, M., & Artman, M. (2001). The New York University Pediatric Heart Failure Index: A new method of quantifying chronic heart failure severity in children. Journal of Pediatrics, 138 (5): 644-648.

9. Dickinson, D.F., & Sambrooks, J.E. (1979). Intellectual performance in children after circulatory arrest with profound hypothermia in infancy. Archives of Disease in Childhood, 54: 1-6.


22 1 Introduction

10. Dittrich, H., Bührer, C., Grimmer, I., Dittrich, S., Abdul-Khaliq, H., & Lange, P.E. (2003). Neurodevelopment at 1 year of age in infants with congenital heart disease. Heart, 89 (4): 436-441.

11. Ekroth, R., Thompson, R.J., Lincoln, C., Scallan, M., Rossi, R., & Tsang, V. (1989). Elective deep hypothermia with total circulatory arrest: changes in plasma creatine kinease BB, blood glucose, and clinical variables. Journal of Thoracic and Cardiovascular Surgery, 97: 30-35.

12. Feldt, R.H., Ewart, J.C., Stickler, G.B., & Weidman, W.H. (1969). Children with congenital heart disease. American Journal of Diseases in Children, 117: 281-287.

13. Forbess, J.M., Visconti, K.J., Bellinger, D.C., Howe, R.J., & Jonas, R.A. (2002). Neurodevelopmental outcomes after biventricular repair of congenital heart defects. Journal of Thoracic and Cardiovascular Surgery, 123 (4): 631-639.

14. Forbess, J.M., Visconti, K.J., Hancock-Friesen, C., Howe, R.C., Bellinger, D.C., & Jonas, R.A. (2002). Neurodevelopmental outcome after congenital heart surgery: Results from an institutional registry. Circulation, 106 (13): I 95 – I 102.

15. Gaynor, J.W., Gerdes, M., Zackai, E.H., Bernbaum, J., Wernovsky, G., Clancy, R.R., Newman, M.F., Saunders, A.M., Heagerty, P.J., D'Agostino, J.A., McDonald-McGinn, D., Nicolson, S.C., Spray, T.L., & Jarvik, G.P. (2003). Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. Journal of Thoracic and Cardiovascular Surgery, 126: 1736-1745.

16. Hamrick, S.E.G., Gremmels, D.B., Keet, C.A., Leonard, C.H., Connell, J.K., Hawgood, S., & Piecuch, R.E. (2003). Neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation after cardiac surgery. Pediatrics, 111 (6): E 671- E 675.

17. Haneda, K., Itoh, T., Togo, T., Ohmi, M., & Mohri, H (1996). Effects of cardiac surgery on intellectual function in infants and children. Cardiovascular Surgery, 4 (3): 303-307.

18. Hoffman, J.I., & Kaplan, S. (2002). The incidence of congenital heart disease. Journal of American College of Cardiology , 39: 1890-1900.

19. Hövels-Gürich, H..H., Seghaye, M.C., Däbritz, S., Messmer, B.J., & von Bernuth, G. (1997). Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. Journal of Thoracic and Cardiovascular Surgery, 114 (4): 578-585.


1 Introduction 23

20. Hövels-Gürich, H.H., Seghaye, M.C., Schnitker, R., Wiesner, M., Huber, W., Minkenberg, R., Kotlarek, F., Messmer, B.J., & von Bernuth, G. (2002). Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation. Journal of Thoracic and Cardiovascular Surgery, 124 (3): 448-458.

21. Hövels-Gürich, H.H., Seghaye, M.C., Sigler, M., Kotlarek, F., Bartl, A., Neuser, J., Minkenberg, R., Messmer, B.J., & von Bernuth, G. (2001). Neurodevelopmental outcome related to cerebral risk factors in children after neonatal arterial switch operation. Annals of Thoracic Surgery, 71 (3): 881-888.

22. Jonas, R.A., Wypij, D., Roth, S.J., Bellinger, D.C., Visconti, K.J., du Plessis, A.J. Goodkin, H., Laussen, P.C., Farrell, D.M., Bartlett, J., McGrath, E., Rappaport, L.J., Bacha, E.A., Forbess, J.M., & del Nido, P. (2003). The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. Journal of Thoracic and Cardiovascular Surgery, 126: 1764-1774.

23. Kern, J.H., Hinton, V.J., Nereo, N.E., Hayes, C.J., & Gersony, W.M. (1998) Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome. Pediatrics, 102 (5): 1148-1152.

24. Kirkham, F.J. (1998). Recognition and prevention of neurological complications in pediatric cardiac surgery. Pediatric Cardiology, 19: 331-345.

25. Lewis, F.J., & Taufic, M. (1953). Closure of atrial septal defects with the aid of hypothermia: experimental accomplishments and the report of one successful case. Surgery, 32: 52-59.

26. Limperopoulos, C., Majnemer, A., Shevell, M.I., Rohlicek, C., Rosenblatt, B., Tchervenkov, C., & Darwish, H.Z.. (2002). Predictors of developmental disabilities after open-heart surgery in young children with congenital heart defects. Journal of Pediatrics, 141 (5): 51-58.

27. Limperopoulos, C., Majnemer, A., Shevell, M.I., Rosenblatt, B., Rohlicek, C., & Tchervenkov, C. (1999). Neurologic status of newborns with congenital heart defects before open-heart surgery. Pediatrics, 103 (2): 402-408.

28. Linde, L.M., Rasof, B., & Dunn, O. (1967). Mental development in congenital heart disease. Journal of Pediatrics, 71: 198-203.


24 1 Introduction

29. Mahle, W.T., Clancy, R.R., Moss, E.M., Gerdes, M., Jobes, D.R., & Wernovsky, G. (2000). Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome. Pediatrics, 105 (5): 1082-1089.

30. Mahle, W.T., Spray, T.L., Wernovsky, G., Gaynor, J.W., & Clark, B.J. (2000). Survival after reconstructive surgery for hypoplastic left heart syndrome: a 15-year experience from a single institution. Circulation, 102: III 136-III 141.

31. Mahle, W.T., Tavani, F., Zimmerman, R.A., Nicolson, S.C., Galli, K.K., Gaynor, W., Clancy, R.R., Montenegro, L.M., Spray, T.L., Chiavacci, R.M., Wernovsky,G., & Kurth, C.D (2002). An MRI study of neurological injury before and after congenital heart surgery. Circulation, 106 (suppl I): I-109 – I- 114.

32. May, L.E. (2001). Pediatric Heart Surgery: A ready reference for professionals. 2nd edition, Milwaukee, Wis: Maxishare.

33. McConnell, J.R., Fleming, W.H., Chu, W.K., Hahn, F.J., Sarafan, L.B., Hofschire, P.J., & Kugler, J.D. (1990). Magnetic resonance imaging of the brain in infants and children before and after cardiac surgery. A prospective study. American Journal of Diseases in Children, 144 (3): 374-378.

34. Miller, G., & Vogel, H. (1999). Structural evidence of injury or malformations in the brains of children with congenital heart disease. Seminars in Pediatric Neurology, 6: 20-26.

35. Miller, G., Tesman, J.R., Ramer, J.C., Baylen, B.G., & Myers, J.L. (1996). Outcome after open-heart surgery in infants and children. Journal of Child Neurology, 11: 49-53.

36. Newburger, J.W., Jonas, R.A., Wernovsky, G., Wypij, D., Hickey, P.R., Kuban, K.C.K., Farrell, D.M., Holmes, G.L., Helmers, S.L., Constantinou, J., Carrazana, E., Barlow, J.K., Walsh, A.Z., Lucius, K.C., Share, J.C., Wessel, D.L., Hanley, F.L., Mayer, J.E., Castaneda, A.R., & Ware, J.H. (1993). A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart-surgery. New England Journal of Medicine, 329 (15): 1057-1064.

37. Newburger, J.W., Wypij, D., Bellinger, D.C., du Plessis, A.J., Kuban, K.C.K., Rappaport, L.A., Almirall, D., Wessel, D.L., Jonas, R.A., & Wernovsky, G. (2003). Length of stay after infant heart surgery is related to cognitive outcome at age 8 years. Journal of Pediatrics, 143: 67-73.


1 Introduction 25

38. Nuutinen, M., Koivu, M., & Rantakallio, P. (1989). Long-term outcome for children with congenital heart defects. Arctic Medical Research, 48: 175-184.

39. O’Dougherty, M., Wright, F.S., Garmezy, N., Lowenson, R.B., & Torres, F. (1983). Later competence and adaptation in infants who survive severe heart defects. Child Development, 54: 1129-1142.

40. O’Dougherty, M., Wright, F.S., Loewenson, R.B., & Torres, F. (1985). Cerebral dysfunction after chronic hypoxia in children. Neurology, 35: 42-46.

41. Oates, R.K., Simpson, J.M., Cartmill, T.B., & Turnbull, J.A.B. (1995 a). Intellectual function and age of repair in cyanotic congenital heart disease. Archives of Disease in Childhood, 72 (4): 298-301.

42. Oates, R.K., Simpson, J.M., Turnbull, J.A.B., & Cartmill,T.B. (1995 b) The relationship between intelligence and duration of circulatory arrest with deep hypothermia. Journal of Thoracic and Cardiovascular Surgery, 110 (3): 786-792.

43. Rappaport, L.A., Wypij, D., Bellinger, D.C., Helmers, S.L., Holmes, G.L., Barnes, P.D., Wernovsky, G., Kuban, K.C.K., Jonas, R.A. & Newburger, J.W. (1998). Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Circulation, 97: 773 – 779.

44. Rasof, B., Linde, L.M., & Dunn, O. (1967). Intellectual development in children with congenital heart disease. Child Development, 38: 1043-1053.

45. Rogers, B.T., Msall, M.E., Buck, G.M., Lyon, N.R., Norris, M.K., Roland, J.M.A., Gingell, R.L., Cleveland, D.C., & Pieroni, D.R. (1995). Neurodevelopmental outcome of infants with hypoplastic left heart syndrome. Journal of Pediatrics, 126 (3): 496-498.

46. Rosenthal, A. (1967). Visual simple reaction time in cyanotic heart disease. American Journal of Diseases in Children, 114: 139-143.

47. Rossi, R., Ekroth, R., Lincoln, C., Jackson, A.P., Thompson, R.J., Scallan, M., & Tsang, V. (1986). Detection of cerebral injury after total circulatory arrest and profound hypothermia by estimation of specific creatine kinase isoenzyme levels using monoclonal antibody techniques. American Journal of Cardiology, 58 (13): 1236-1241.

48. Rossi, R., vander Linden, J., Ekroth, R., Scallan, M., Thompson, R.J., & Lincoln, C. (1989). No flow or flow: a study of ischemic marker creatine kinase BB after deep hypothermic procedures. Journal of Thoracic and Cardiovascular Surgery, 98: 193-199.


26 1 Introduction

49. Scallan, M.J.H. (2003). Brain injury in children with congenital heart disease. Paediatric Anesthesia, 13: 284-293.

50. Sharma, R., Choudhary, S.K, Mohan, M.R., Padma, M.V., Jain, S., Bhardwaj, M., Bhan, A., Kiran, U., Saxena, N., & Venugopal, P. (2000). Neurological evaluation and intelligence testing in the child with operated congenital heart disease. Annals of Thoracic Surgery, 70: 575-581.

51. Silbert, A., Wolff, P.H., Mayer, A., Rosenthal, A., & Nada, AS. (1969). Cyanotic heart disease and psychological development. Pediatrics, 43 (2): 192-200.

52. Treasure, T., Naftel, D.C., Conger, K.A., Garcia, J.H., Kirklin, J.W., & Blackstone, E.H. (1983). The effect of hypothermic circulatory arrest time on cerebral function, morphology and biochemistry. Journal of Thoracic and Cardiovascular Surgery, 86: 761-770.

53. Uzark, K., Lincoln, A., Lamberti, J.J., Mainwaring, R.D., Spicer, R.L., & Moore, J.W. (1998). Neurodevelopmental outcomes in children with Fontan repair of functional single ventricle. Pediatrics, 101 (4): 630-633.

54. Van Hoecke, E., & Dhont, M. (2004). Aangeboren hartaandoening: verwerking door het kind en zijn ouders [Congenital heart disease: coping mechanisms of the child and its parents]. Tijdschrift voor Geneeskunde, 60 (21):1548-1554.

55. Visconti, K.J., Bichell, D.P., Jonas, R.A., Newburger, J.W., & Bellinger, D.C. (1999) Developmental outcome after surgical versus interventional closure of secundum atrial septal defect in children. Circulation, 100 (19): 145-150.

56. Wells, F.C., Coghill, S., Caplan, H.L., Lincoln, C., & Kirklin, J.W. (1983). Duration of cardiopulmonary arrest does influence the psychological development of children after cardiac operation in early life. Journal of Thoracic and Cardiovascular Surgery, 86: 823-831.

57. Wernovsky, G., Stiles, K.M., Gauvreau, K., Gentles, T.L., duPlessis, A.J., Bellinger, D.C., Walsh, A.Z., Burnett, J., Jonas, R.A., Mayer, J.E., & Newburger, J.W. (2000) Cognitive development after the Fontan operation. Circulation, 102 (8): 883-889.

58. Wray, J., & Sensky, T. (1999). Controlled study of preschool development after surgery for congenital heart disease. Archives of Disease in Childhood, 80: 511-516.

59. Wray, J., & Sensky, T. (2001). Congenital heart disease and cardiac surgery in childhood: effects on cognitive function and academic ability. Heart, 85 (6): 687-691.


1 Introduction 27

60. Wright, M., & Nolan, T. (1994). Impact of cyanotic heart disease on school performance. Archives of Disease in Childhood, 71: 64-70.


28 1 Introduction

Table 2: An overview of neuropsychological studies on children with congenital heart

defects


1 Introduction 29


30 1 Introduction


1 Introduction 31


32 1 Introduction


1 Introduction 33


34 1 Introduction


1 Introduction 35


36 1 Introduction


1 Introduction 37


38 1 Introduction


1 Introduction 39


40 1 Introduction


1 Introduction 41


42 1 Introduction


1 Introduction 43

1.3 Goals of the thesis and methodology

Many studies covering neurodevelopment were conducted on infants and children 1 to 4 years after surgery. However, at that age it is unclear whether the neurodevelopmental delay is due to a maturation delay or to a more permanent impairment. The chapters in this thesis aimed to specify the functional outcome in children with a surgically corrected CHD, 6 to 12 years postoperatively as measured by intellectual and neuropsychological performance. Behavioral and emotional data were collected using validated self-report questionnaires. Both parents and children were used as informants. G o a l s o f t h e t h e s i s

Describing the neuropsychological profile in children with surgically corrected CHD 6 to 12 years postoperatively. Chapter 2: Neuropsychological performance in school-aged children with a surgically corrected congenital heart disease. Journal of Pediatrics, in press.

Comparing functional outcome in cyanotic CHD, acyanotic CHD and healthy children. Chapter 3: Intellectual, neuropsychological and behavioral functioning in children with tetralogy of Fallot. Journal of Thoracic and Cardiovascular Surgery, 2007; 133:449-455.

Identifying medical and surgical predictors of neuropsychological deficits in school- aged children with a surgically corrected congenital heart disease. Chapter 4: Medical and surgical predictors of neuropsychological deficits in school aged children with a surgically corrected congenital heart disease.

Describing the behavior, the emotional functioning, and self-perception of children with surgically corrected CHD 6 to 12 years postoperatively. Chapter 5: Behavior and self-perception in children with a surgically corrected congenital heart disease. Journal of Developmental and Behavioral Pediatrics, in press.

Creating the possibility for parents to report on cognitive deficits by means of a questionnaire. Chapter 6: Do parental ratings on cognition reflect neuropsychological outcome in congenital heart disease? Submitted for publication.

These goals will be further discussed within each chapter as well as in the general discussion.


44 1 Introduction

Through description of the mid-term functional outcome of children with surgically corrected CHD and the inclusion of both the child’s and the parent’s view, we hope to identify a profile typical for these children, that is easy to recognize by pediatricians, cardiologists, cardiac surgeons, psychologists and parents. The neuropsychological and behavioral characteristics could and should lead to specialized and tailored interventional programs. M e t h o do l o gy

P a t i e n t s

Patients with various congenital heart diseases, operated in the Ghent University Hospital, between 1995 and 1999, with a birth weight > 2000g (we chose this weight in order to include as many patients as possible), without perinatal problems (asphyxia or infections such as toxoplasmosis, rubella, HIV) and without non-cardiac malformations or genetic abnormalities (Down syndrome, Velocardiofacial syndrome, and Di George) were contacted and invited to participate in the study (n = 163). Several candidates had moved and could not be located (n = 17). Various reasons were given by non participators: presence of a developmental disorder (n= 2, one boy with autism, one boy with a severe learning disorder), testing being too time consuming (n= 27), awaiting new cardiac surgery for the child (n = 2), not wanting to confront the child with something that happened a long time ago (n = 19), stating that the child has no cognitive problems and participating would imply that he or she does (n = 8). Reasons for not participating remained unclear in 31 cases that did not respond in any way to the invitation. In total, 57 patients were included of which we selected only those that underwent an open-heart procedure (n= 43; 21 girls, 22 boys). We compared the total CHD-group to healthy controls and the cyanotic CHD-group (n=26) to the acyanotic CHD-group (n=17). In the total sample, two children were born at gestational age respectively 25 weeks (birth weight 958g) and 29 weeks (birth weight 1930g). These children were excluded from further analysis due to possible confounding variables such as prematurity and very low birth weight. In the selected sample of 43 children who underwent an open-heart procedure, one child was born at gestational week 32 with a birth weight of 2250g, all other children were born between 37 and 40 weeks gestational age. Lowest birth weight noted in this group was 2450 g. In the control group, all children were born between 37 and 40 weeks of gestation with lowest birth weight noted 2650g. For each child in the patient group, a healthy sex, age-, and educational level matched control was included. Local school boards were contacted with the question to select a child with a specific sex, age, and educational level of mother and father, matching the patient’s characteristics. Inclusion criteria were the same as for the patient group (birth weight > 2000 g, without perinatal problems (asphyxia or


1 Introduction 45

infections such as toxoplasmosis, rubella, HIV) and without non-cardiac malformations or genetic abnormalities (Down syndrome, Velocardiofacial syndrome, and Di George). Parents of the healthy children completed a questionnaire on birth length and weight, gestational age and Apgar scores. They also completed the Child Behavior Checklist, in which they provided information on the need for special education, learning disorders or other problems at school and physical or mental disorders. Children with a positive rate on these items were excluded from the study. Demographics on the different groups can be found in following tables. The original sample consisted of 57 children:

Variable Patient group (n=57)

Control group (n= 57)

Sex 29♂ 28 ♀ 29 ♂ 28 ♀

Age 8y10m ± 1y6m 8y10m± 1y6m

Education father (years) 12.8 ± 2.0 14.5 ± 3.3

Education mother (years) 13.0 ± 2.8 14.0 ± 2.6

In Chapter 2 we selected only those children who underwent open heart surgery.



Sex 22 ♂ 21 ♀ 22 ♂ 21 ♀

Age 8y8m ± 1y6m 8y11m± 1y7m




46 1 Introduction

In Chapter 3 we selected the children with tetralogy of Fallot, an acyanotic group, and a control group

Group TOF-group (n=18)

Acyanotic group (n=17)


Sex 10 ♂ 8 ♀ 7 ♂ 10 ♀ 10 ♂ 8 ♀ Age 8y 3m ± 1y 6m 9y 2m ± 1y 6m 8y 4m ± 1y 6m Education father (years) 13.0 ± 2.2 12.9 ± 2.0 14.0 ± 3.1 Education mother (years) 12.9 ± 1.6 13.0 ± 2.7 13.6 ± 2.8

In Chapter 5 the total group that underwent open heart surgery was included.



Sex 22 ♂ 21 ♀ 22 ♂ 21 ♀

Age 8y8m ± 1y6m 8y11m± 1y7m



Only children > 8years were studied in the second part of chapter 5.



Sex 9 ♂ 14 ♀ 9 ♂ 14 ♀

Age 9y6m ± 1y2m 9y7m ± 1y2m



I n t e l l e c t u a l a n d n e u r o p s y c h o l o g i c a l a s s e s s m e n t

- The child was tested with a short form of the Wechsler Intelligence Scale for Children -3rd edition, Dutch version (WISC-III NL). The short form included 2 verbal subtests Information and Vocabulary, and 2 performance subtests Picture Completion and Block Design (Grégoire, 2000). A deviation IQ was calculated using the procedure suggested by Sattler (1995). The formula for converting the scaled scores into an IQ-score: 1.7 (Xsf) + 34, where Xsf is the sum of the subject’s scaled scores included in the short form. The reliability coefficient of the short form Information, Vocabulary, Block Design and Picture completion is .91. This value is


1 Introduction 47

very close to the reliability of the Full Scale IQ (.95). This coefficient is high and sufficient for a clinical practice (Grégoire, 2000). - The neuropsychological battery consisted of all core subtests of the NEPSY (a developmental neuropsychological assessment) measuring Attention and Executive Functioning, Memory, Language, Visual-spatial Skills and Sensorimotor Functioning (Korkman et al, 1998). B e h a v i o r a l f u n c t i o n i n g

P a r e n t a l r e p o r t s

Parents were asked to complete several questionnaires in order to describe the functional status, behavior, and cognitive functioning of their child. - New York Heart Association Class – modified (NYHA-class) The New York Heart Association Class classifies the functional status of the child (Bruns et al, 2001). - The Achenbach Child Behavior Checklist (CBCL) This checklist reports on the presence of behavioral, social, and emotional problems in 4 to 18-year old children as reported by their parents (Achenbach, 1991; Verhulst et al, 1990). Both competence and problem scales were used. - Questionnaire on cognitive skills Parents completed a questionnaire that was constructed by Miatton and Vingerhoets based on the adult subjective complaints questionnaire (Newman et al, 1989) to trace the kind and severity of cognitive difficulties a child with CHD might experience. The questionnaire includes 15 questions concerning attention skills (sustained and divided attention), memory functioning (recall and learning), problem solving strategies (planning and executing) and motor skills (fine and gross). The parent is asked to indicate the frequency of the cognitive problem (never, sometimes, mostly, and always). C h i l d r e p o r t

The self-report questionnaires were only completed by children ≥ 8 years. - Self-perception profile for Children (SPP-C) This scale assesses perceived competence in School Performance, Social Acceptance, Athletic Activities, Physical Appearance, Behavior, and Global Self-worth (Harter, 1985). The children completed a supplementary Perceived Motor Competence Scale, measuring both their impression of their motor skills and the importance of motor functions in daily life (Van Rossum & Vermeer, 2000). - Children’s Depression Inventory (CDI) This 27-item questionnaire indicates the presence and severity of a depression in 8 to 17-year old children (Kovacs, 1992; Timbremont & Braet, 2002).


48 1 Introduction

- The State- Trait Anxiety Inventory for Children (STAI-C) This self-report inventory identifies state anxiety in 8 to 15-year old children and contains 20 sentences referring to vegetative and cognitive symptoms of anxiety present at that moment (Spielberger et al, 1973; Bakker et al, 1989).

2 Neuropsychological performance in school-aged children with a surgically corrected congenital heart disease 49

2 N e u r o p s y c h o l o g i c a l p e r f o r m a n c e i n s c h o o l - a g e d c h i l d r e n w i t h a s u r g i c a l l y c o r r e c t e d c o n g e n i t a l h e a r t d i s e a s e

Marijke Miatton, Daniël De Wolf, Katrien François, Evert Thiery, Guy

Vingerhoets Journal of Pediatrics 2007, in press

A b s tr ac t

Objective: As surgical management of children with congenital heart disease (CHD) advanced, developmental outcome became the main focus of contemporary research. In this study, we specify the cognitive profile of children with CHD, six to twelve years postoperatively. Study design: Patients with CHD (n=43, mean age 8y8m) and healthy controls (n=43, mean age 8y11m), were examined with an abbreviated intelligence scale (WISC-III) and a developmental neuropsychological assessment battery (NEPSY). Results: We identified significantly lower scores for the CHD-group on Estimated Full Scale IQ (p<.01). Neuropsychological assessment revealed lower scores for the CHD-group on the cognitive domains of sensorimotor functioning (p<. 001), language (p < .001), attention and executive functioning (<.05) and memory (p<.05). Children with CHD displayed more impulsive test behavior than healthy peers. No differences on IQ or cognitive domains were found between the cyanotic and the acyanotic CHD-group. Conclusions: Six to twelve years postoperatively, children with CHD display a neuropsychological profile with mainly mild motor deficits and subtle difficulties with language tasks. Attention/executive functioning and memory also appear involved, but to a lesser degree. Long-term follow-up of children with surgically corrected CHD, even when hemodynamically successful, is warranted, as they are at risk for neurodevelopmental delay at school age.


50 2 Neuropsychological performance in school-aged children with a surgically corrected congenital heart disease

I n t r o d uc t i o n

The incidence of congenital heart disease (CHD) in the Western industrialized world is estimated at 12 per 1000 live births (1). Significant advances in surgical management and decreases in mortality and morbidity rates have made functional outcome the primary focus of contemporary research. Follow-up studies have identified developmental and neurological abnormalities in as many as 25% of survivors. Neurological evaluation mostly revealed deficits in neurocognitive (language, attention) or motor functions (balance, hopping) (2). On developmental testing, children with CHD showed poorer hand-eye coordination and lower scores on locomotor functioning, personal/social, and speech and hearing scales than healthy control subjects (3). Assessment of IQ in school-aged children with CHD showed scores within the expected range (4, 5), although lower than in the general population (6). Neuropsychological assessment was mostly performed on isolated diagnostic groups and revealed problems on several cognitive functions (7-16). The purpose of the present study is to characterize the neuropsychological outcome of school-aged children with a surgically corrected cyanotic or acyanotic CHD and compare their performances to those of age and sex matched healthy controls. In contrast to most studies, enrollment of children was not limited to those with a specific diagnosis, but covered the whole spectrum of CHD, in order to draw conclusions on the neuropsychological functioning of children with CHD in general and not to link specific neurocognitive profiles to specific diagnoses. We tried to identify differences in neuropsychological outcome between cyanotic and acyanotic CHD. We studied an older group than in most studies, because the neurological status shortly after surgery is well known, while the neuropsychological profile of school-aged children with surgically corrected CHD is still to be characterized.



P a t i e n t s a n d M e t h o d s

P a t i e n t c h a r a c t e r i s t i c s a n d m e d i c a l d a t a

Patients with various congenital heart diseases, operated in the Ghent University Hospital, between 1995 and 1999, with a birth weight > 2000g, without perinatal problems and without non-cardiac malformations or genetic abnormalities (Down syndrome, Velocardiofacial syndrome, and Di George) were contacted and invited to participate in the study (n = 163). Several candidates had moved and could not be located (n = 17). Various reasons were given by non participators: presence of a developmental disorder (n= 2, one boy with autism, one boy with a severe learning disorder), testing being too time consuming (n= 27), awaiting new cardiac surgery for the child (n = 2), not wanting to confront the child with something that happened a long time ago (n = 19), stating that the child has no cognitive problems and participating would imply that he or she does (n = 8). Reasons for not participating remained unclear in 31 cases that did not respond in any way to the invitation. All children with TOF and all other children showing characteristic features of genetic abnormalities at birth had a genetic screening (Fluorescence In Situ Hybridization, FISH) to exclude for Di George/Velocardiofacial syndrome. In total, 57 patients were included in the project of which we selected only those patients that underwent an open-heart procedure (n=43; 21 girls, 22 boys). We compared the total CHD-group to the healthy controls and the cyanotic CHD-group (n=26) to the acyanotic CHD-group (n=17). For each child in the patient group, a healthy sex-, age-, and educational level matched control was included. The healthy children were contacted through their school boards. All parents gave written informed consent. At the time of testing, all children (i.e. the total CHD-group and healthy controls) attended school full time and according to their parents they participated actively in sports and social activities. We calculated the Hollingshead Four Factor Index of Social Status to quantify the socioeconomic status of each family. This index uses education, occupation, sex, and marital status to determine a composite social status. The score was computed by multiplying the Occupation scale value by a weight of 5 and the Education scale by 3, and summing these products. The raw scores range from 8 to 66, with higher scores reflecting higher socioeconomic status (17). The local Ethical Committee approved the study. Procedures were in accordance with the recommendations found in the Helsinki Declaration of 1975 (18). Medical data were collected from the patients’ files. We included birth weight, and length, Apgar scores immediately after birth and after 10 minutes. All children underwent an open-heart operation with full flow cardiopulmonary bypass under moderate hypothermia (25°C-33°C).



N e u r o p s y c h o l o g i c a l a s s e s s m e n t

After agreeing to participate, children were invited for a neuropsychological assessment of 2 to 3 hours duration. The child was tested with a short form of the Wechsler Intelligence Scale for Children -3rd edition, Dutch version (WISC-III NL). The short form included 2 verbal subtests Information and Vocabulary, and 2 performance subtests Picture Completion and Block Design (19). A deviation IQ was calculated using the procedure suggested by Sattler (20). On subtest level a mean performance of 10 (SD= 3) is expected. Mean Estimated Full Scale IQ is 100 (SD= 15). The neuropsychological battery consisted of all core subtests of the NEPSY (a developmental neuropsychological assessment). The NEPSY tests the child’s neuropsychological development in 5 functional domains in order to detect subtle deficiencies, within and across these functional domains, which can interfere with learning in preschool and school-aged children (21). In the domain Attention and Executive Functioning, children had to perform 3 tasks. The subtest Tower measures nonverbal planning and problem solving. Auditory Attention and Response Set tests vigilance, sustained auditory attention and the ability to shift and maintain new and complex sets. The subtest Visual Attention reports on speed and accuracy of selectively focusing and maintaining attention on a visual target. The domain Memory included both verbal (Narrative Memory, Memory for Names) and visual memory tasks (Memory for Faces). The subtests Phonological Processing (phonemic awareness), Speeded Naming (access to and production of names of recurring colors, sizes, and shapes), and Comprehension of Instructions (ability to process and respond quickly to verbal instructions of increasing complexity) formed the domain Language. Visual-spatial Skills were assessed by 2 subtests: Arrows (line orientation and directionality) and Design Copy (ability to copy two-dimensional geometric figures). Fingertip Tapping (finger dexterity and motor speed), Imitation of Hand/Finger Positions (ability to imitate hand/finger positions), and Visuomotor Precision (fine motor skills, hand-eye coordination) were the tasks to perform in the domain Sensorimotor Functioning. A mean performance on the domains is 100 (SD 15), on subtest level a mean performance of 10 (SD 3) is expected.

S t a t i s ti c a l A n al y s i s

Statistical analyses were performed using the SPSS for Windows statistical software package (version 12.0). Demographics (age at the moment of testing, sex, and educational level of both parents, Hollingshead Index), medical characteristics (birth weight and length, Apgar scores), and outcome measures (Estimated IQ, NEPSY) were compared between the total CHD-group and the healthy control group. Nominal data were analyzed with Chi-square statistics. Normality was checked by Kolmogorov-Smirnov tests. If the data were not normally distributed, the non-



parametric Wilcoxon Signed Ranks test was used. For normally distributed data, MANOVA’S were used with group (total CHD-group versus healthy control group, cyanotic CHD-group versus acyanotic CHD-group) as a between subject factor, the WISC-III subtests and the Estimated Full Scale IQ, the NEPSY domains and the NEPSY subtests as dependent variables, and educational level of the father as covariate. R e s ul t s


The mean age at testing of the total CHD-group was 8y8m ± 1y6m. As a result of careful matching, no significant group differences on sex and age at testing were found between the total CHD-group and the healthy control group. There was a significantly lower length at birth (p<.05) in the total CHD-group compared to the healthy control group. We did not find significant differences in Apgar-scores between these groups. No group differences were found on maternal level of education or on socioeconomic status, as rated by the Hollingshead Four Factor Index. The majority of children came from middle class families (skilled craftsmen, clerical and sales workers). We did find a lower paternal educational level in the CHD-group, so this variable was entered as a covariate in all statistical analyses. We divided the CHD-group in a cyanotic (n=26) and an acyanotic CHD-group (n=17). No differences on demographic, medical, or socioeconomic variables could be identified between these patient groups. Medical data are presented in Table 1. Demographic and socioeconomic results are summarized in Table 2.

Table 1. Medical characteristics of the patient and control group



p Cyanotic group (n=26)


p

Sex 22 ♂ 21 ♀ 22 ♂ 21 ♀ .829‡ 15 ♂ 11 ♀ 7♂ 10 ♀ .889‡

Birth weight (g)

3094 ± 741 3385 ± 600 .060 3018 ± 804 3212 ± 638 .420

Birth length (cm)

48.9 ± 3.1 50.4± 2.4 .019* 48.7 ± 3.4 49.2 ± 2.8 .648

Apgar immediately after birth

< 4: 15.8%

4 – 7: 0%

7 –10: 84.2%

< 4: 6.5%

4 – 7: 0%

7 – 10:

.059¥ < 4: 27.3%

4 – 7: 0%

7 – 10: 72.7%

< 4: 0%

4 – 7: 0%

7 – 10: 100%

.351¥





p Cyanotic group (n=26)


p

93.5%

Apgar after 10 min

< 4: 10.5%

4 -7: 0%

7-10: 89.5 %

< 4: 0%

4 – 7: 3.2 %

7 – 10:

96.8%

.157¥ < 4: 18.2%

4 -7: 0%

7-10: 81.8 %

< 4: 0%

4 – 7:0%

7 – 10: 100%

.545¥

†: degrees of freedom =1, level of significance *p< .05, **p< .001 ‡: χ² test, ¥: Wilcoxon signed-rank test


On the short form intelligence scale, we found a significantly lower Estimated Full Scale IQ for the total CHD-group (p<. 01). Two of the subtests included were significantly lower in the patient group: Picture Completion (p<. 01) and Vocabulary (p<.05). Children with CHD performed significantly lower on the domains of Sensorimotor Functioning (p<.001) and Language (p<.001) than healthy controls. Each subtest included in both domains yielded significantly lower results. Attention and Executive functioning (p< .05) as well as Memory (p<.05) also displayed significantly lower performances in the CHD-group. Visual-spatial skills did not elicit group differences. Results on all included subtests are summarized in Table 2. Boxplots of the group differences on estimated IQ, Sensorimotor Functioning, and Language can be found in Figure 1. In Figure 2 and Figure 3, boxplots on the subtests of the domain Sensorimotor Functioning and Language can be found. No significant differences between the cyanotic and the acyanotic CHD group emerged on the intellectual and neuropsychological evaluation.



Table 2. Demographics, mean performances, and standard deviations on IQ and NEPSY, F,

and p-value.

Variable Patient group n=43

Control group n=43

F¥ p

Age 8y8m ± 1y6m 8y11m± 1y7m .644 .829 Sex 22 ♂ 21♀ 22 ♂ 21 ♀ .047 † .571 Education father (years)

12.9 ± 2.0 14.3 ± 3.4 4.86 .031*

Education mother (years)

13.0 ± 1.9 13.7 ± 2.9 1.70 .197

Mean Hollingshead SES

32.4 ± 8.4 35.6 ± 11.2 2.80 .135

INTELLIGENCE Estimated Full Scale IQ Picture completion Block Design Information Vocabulary

95.6 ± 15.4 8.4 ± 3.7 9.2 ± 3.0

10.3 ± 2.8 9.6 ± 2.3

107.0 ± 15.1 10.6 ± 3.5 10.1 ± 2.9 11.7 ± 2.6 11.5 ± 2.7

.833 8.26 1.67 3.57 6.93

.005* .005* .200 .062 .010*

NEPSY Attention and executive functioning: tower auditory attention and response set visual attention Memory: memory for faces memory for names total over trials

(max 24) recall (max 8)

narrative memory Language: phonological processing speeded naming

time (sec) errors

comprehension of

112.5 ± 10.1

12.8 ± 2.2 12.3 ± 1.2

9.8 ± 2.8

98.4 ± 14.0 10.3 ± 3.1 8.7 ± 3.4

12.9 ± 5.1

4.6 ± 2.3

10.5 ± 3.0

102.0 ± 11.8 12.0 ± 3.0 8.9 ± 2.2 135 ± 54 0.9 ± 1.3 10.5 ± 1.9

117.8 ± 9.2

14.0 ± 2.1 12.1 ± 1.3

11.0 ± 2.3

105.7 ± 12.3 10.6 ± 3.1 11.1 ± 2.4

16.5 ± 4.1

5.9 ± 1.8

10.8 ± 1.9

115.8 ± 14.0 13.9 ± 2.7 10.8 ± 2.3 145 ± 57 0.3 ± 0.5 12.5 ± 2.2

5.80

5.31

-.850 ‡

5.30 6.56 .443

12.72

-3.12 ‡

6.51

.301 20.0 7.06

11.89 5.60

-2.76‡ 15.65

.018*

.024* .395

.024* .012* .508

.001**

.002*

.013*

.585 <.001**

.010*

.001*

.020*

.006* <.001**



Variable Patient group n=43

Control group n=43

F¥ p

instructions Visual-spatial skills design copy arrows Sensorimotor functioning imitating hand positions fingertip tapping visuomotor precision

time (sec) errors

115.0 ± 15.7 13.9 ± 3.0 10.9 ± 2.8 88.8 ± 13.4

8.5 ± 2.8

9.5 ± 1.5 7.3 ± 3.2 135 ± 54

19.8 ± 20.9 (range 0-76)

120.2 ± 12.7 14.7 ± 2.5 11.7 ± 2.5

101.1 ± 9.6

11.4 ± 2.3

10.5 ± 1.8 9.1 ± 2.2 145 ± 48

4.95 ± 7.9

1.27 .593 .797

18.59

18.61

-2.48 ‡ 7.17 .455

-3.90 ‡

.263 .444 .375

<.001**

<.001**

.013*

.009* .502

<.001**

¥ : degrees of freedom [1, 81], †: ?² value , ‡: Kruskall Wallis test , SES: socioeconomic status, level of significance *p< .05, ** p< .001

Figure 1. Boxplot group differences on Estimated Full Scale IQ, domain scores of

Sensorimotor Functioning and Language



Figure 2. Boxplots on group differences of all subtests of the domain Sensorimotor

Functioning



Figure 3. Boxplots on group differences of all subtests of the domain Language

D i s c u s s i o n

The current study results indicate a significant relation between surgically corrected CHD and specific neurocognitive difficulties during school age. In accordance with previously published studies (4, 5, 6), we found the estimated intellectual capacities of children with surgically corrected CHD to fall within the expected range, although significantly lower than in our healthy group. Since it was not our intention to replicate IQ-findings, we used only a short form intelligence battery. Nevertheless, one can appreciate the differences we found on subtest level. Children with CHD showed significantly worse performances on the verbal subtest Vocabulary, in accordance with studies that performed Full Scale IQ testing (7). This lower score on the verbal subtest reflects the deficits in expressive and receptive language that children with CHD display (10, 11). Picture Completion also yielded significant differences. This subtest demands visual recognition and asks the child to compare the given picture with the image in their visual long-term memory. We will further explain the lower performances on the short form IQ-subtests Vocabulary and Picture Completion by means of the neuropsychological results. On the neuropsychological evaluation, the most striking deficits are found on sensorimotor functioning and language. We found up to 25% of the children with CHD to perform worse than expected on motor tasks. Children with CHD had significantly reduced skills to imitate hand and finger positions, were slower on motor tasks, showed worse hand-eye coordination, less accuracy in fine visuomotor skills and they used an impulsive strategy compared to the healthy control group.



Inefficient processing of tactile and kinesthetic information seems the most plausible explanation for these poor sensorimotor performances in the CHD-group (21). The slowing down in more complex motor tasks and worse hand-eye coordination has been repeatedly reported before (7, 11, and 12). In an attempt to identify the cause of these sensorimotor deficits, recent research revealed children with preoperative hypoxemia in infancy to be at higher risk for motor dysfunction than children with cardiac insufficiency (22). In the brain, the basal ganglia are most sensitive to hypoxia and ischemia. Previous studies even demonstrated decreases in the basal ganglia N-acetylaspartate levels to be correlates for neuropsychological sequelae as for instance motor speed (23). Both findings lead to the suspicion of the involvement of the basal ganglia in the motor deficits found in our study. In addition, hypoxia-ischemia has also been considered as a major cause for the occurrence of an important white matter disease called periventricular leukomalacia (PVL) that results in neurodevelopmental delay (24), and occurs in over 50% of neonates that underwent cardiac surgery (25). Children with obvious neurological dysfunctions were excluded in this study; however, we did not dispose of brain imaging results, which leaves the presence of periventricular leukomalacia or other brain damage in our study group unknown. Future functional MRI studies can be useful in clarifying the relationship between motor deficits and brain (dys) functions of the child with CHD. A second neuropsychological function in which children with CHD performed significantly lower is language. At age 2 years 5 months, delays of 2 to 4 months in language and communicative skills have been reported (10). However, at that age it remains unclear whether this deficit later forms a specific delay, or whether it is part of broader general cognitive impairment. Results on the NEPSY domain Language in our study, give reason to believe that language remains a specific area of concern in older children with surgically corrected CHD. The CHD-group strongly differed from the healthy control group on all language related subtests as well as on the short form IQ-subtest Vocabulary. These children had lower phonological awareness, showed a deficient strategy to gain access to names of color, size, and shape, and lacked the ability to process and respond quickly to verbal instructions of increasing difficulty. During the subtest Speeded Naming, children with CHD again displayed an impulsive strategy, as revealed by a shorter time to complete the task compared to healthy controls, yet accompanied by more errors. These results corroborate with studies in children with TGA, in which dysfunction of speech was found in 40% (11). In infants with TGA or VSD, expressive language was found to be reduced in 34.4%; receptive language seemed defective in 28.1% (26). Poorer performances in reading and spelling are recognized as well (9). Possibly this deficient access to names of color, size, and shape, suggests a deficient retrieval of sound-symbol associations and spoken-written word connections involved in reading acquisition (21).



In contrast to previous studies (26, 27), the children with CHD showed significantly lower results on Memory. The subtest Memory for Names as well as short form IQ-subtest Picture Completion specifically demands a cross-modal association between visual and semantic information, which is particularly difficult for children with CHD. They display difficulties with both learning and recalling the names associated with the faces presented. Further, our results indicate lower performances for the CHD-group on the subtests Tower and Visual Attention. Focused auditory attention revealed no problems, but behavioral observation during the testing again revealed poor impulse control on the subtest Tower. Impulsivity in behavior has been previously reported in children with acyanotic CHD (21). Another explanation to bear in mind is a deficiency in frontal lobe functioning, which has been postulated before in adult patients with CHD (28). Concerning Visual Attention, several factors such as poor hand-eye coordination or impulsive strategy might have caused the lower performances in the CHD-group. In contrast to previous studies (16), visual-spatial skills did not elicit differences between the CHD-group and the healthy controls. The children had no problems copying designs and estimating line orientation and directionality. Although it is expected that, due to the difference in severity of the symptoms, cyanotic forms of CHD result in lower functional outcome than acyanotic forms of CHD (9), in this study, we could not identify any differences on the intellectual and neuropsychological evaluation between the cyanotic and the acyanotic CHD-group, which is supported by other clinical studies (5, 8). The current study should be interpreted in light of certain limitations. First, enrollment was voluntary which creates a selection bias. Possibly the small sample size prevented us finding significant differences between the cyanotic and acyanotic CHD group. Second, we did not include a “sick” control group and, thus are unable to report on the impact of factors such as hospitalization, school absence, restrictions on sports/social activities and overprotection by parents on neuropsychological functioning. Future studies should enhance this factor, in order to clarify the respective contribution of post surgery restrictions or of surgery itself to adverse neuropsychological outcome. Impulsive test behavior was observed and objectified in the CHD-group. These differences were observed throughout the group and were not merely caused by a few individual cases. Previously studied broad cognitive functions can now be narrowed down to specific deficits and we can now rate the degree of these relative deficits. This specification in the neuropsychological profile might lead to interventional programs tailored to the child’s needs, significantly improving its functional cognitive outcome. In future, functional magnetic resonance imaging can elucidate the involvement of specific brain areas such as basal ganglia in the neuropsychological deficits we observed.



R e f e r e n c e s

1. Hoffman JI. Incidence of congenital heart disease: I. Postnatal incidence.

Pediatr Cardiol 1995; 16: 103-113.

2. Bellinger DC, Wypij D, Kuban KCK, Rappaport LA, Hickey PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999; 100: 526-532.

3. Wray J, Sensky T. Controlled study of preschool development after surgery for congenital heart disease. Arch Dis Child 1999; 80: 511-516.

4. Dickinson DF, Sambrooks JE. Intellectual performance in children after circulatory arrest with profound hypothermia in infancy. Arch Dis Child 1979; 54: 1-6.

5. Haneda K, Itoh T, Togo T, Ohmi M, Mohri H. Effects of cardiac surgery on intellectual function in infants and children. Cardiovasc Surg 1996; 4: 303-307.


Wright M, Nolan T. Impact of cyanotic heart disease on school performance. Arch Dis Child 1994; 71: 64-70.

7. Oates RK, Simpson JM, Cartmill TB, Turnbull JAB. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child 1995; 72: 298-301.

8. Wray J, Sensky T. Congenital heart disease and cardiac surgery in childhood: effects on cognitive function and academic ability. Heart 2001; 85: 687-691.

9. Bellinger DC, Rappaport LA, Wypij D, Wernovsky G, Newburger JW. Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries. J Dev Behav Pediatr 1997; 18: 75-83.

10. Hövels-Gürich HH, Seghaye MC, Schnitker R, Wiesner M, Huber W, Minkenberg R, et al. Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 2002; 124: 448-458.

11. Hövels-Gürich HH, Seghaye MC, Däbritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114: 578-585.




13. Limperopoulos C, Majnemer A, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov C, et al. Predictors of developmental disabilities after open-heart surgery in young children with congenital heart defects. J Pediatr 2002; 141: 51-58.

14. Miatton M, De Wolf D, François K, Thiery E, Vingerhoets G. Neurocognitive consequences of surgically corrected congenital heart defects: A review. Neuropsychol Rev 2006; 16: 65-85.

15. Bellinger DC, Wypij D, duPlessis AJ, Rappaport LA, Jonas RA, Wernovsky G, et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003; 126: 1385-96.

16. Hollingshead AB. Four Factor Index of Social Status. New Haven, CT: Yale University, Department of Sociology, 1975.

17. World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997; 277: 925-926.

18. Grégoire, J. Comparison of three short forms of the Wechsler Intelligence Scale for children – Third Edition (WISC-III). Eur Rev Appl Psychol 2000; 50, 437-441.

19. Sattler J. Assessment of children, 3rd edition. San Diego, CA: Author; 1992.

20. Korkman M, Kirk U, Kemp S. NEPSY. A developmental neuropsychological assessment. The Psychological Corporation. A Harcourt Assessment Company; 1998.

21. Hövels-Gürich H, Konrad K, Skorzenski D, Nacken C, Minkenberg R, Phys D, et al. Long-term neurodevelopmental outcome and exercise capacity after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy. Ann Thorac Surg 2006; 81: 958-967.

22. Ariza M, Junqué C, Mataro M, Poca M, Bargallo N, Olondo M, et al. Neuropsychological correlates of basal ganglia and medial temporal lobe NAA/Cho reductions in traumatic brain injury. Arch Neurol 2004; 61: 541-544.

23. Fan LW, Lin S, Pang Y, Lei M, Zhang F, Rhodes P, et al. Hypoxia-ischemia induced neurological dysfunction and brain injury in the neonatal rat. Behav Brain Res 2005; 165: 80-90.



24. Galli K, Zimmerman R, Jarvik G, Wernovsky G, Kuypers M, Clancy R, et al . Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2004; 127: 692-704.

25. Hövels-Gürich H, Seghaye M, Sigler M, Kotlarek F, Bartl A, Neuser J, et al. Neurodevelopmental outcome related to cerebral risk factors in children after neonatal switch operation. Ann Thorac Surg 2001; 71: 881-888.

26. Visconti K, Bichell D, Jonas R, Newburger J, Bellinger D. Developmental outcome after surgical versus interventional closure of secundum atrial septal defect in children. Circulation 1999; 100 suppl II: 145-150.

27. Daliento L, Mapelli D, Russo G, Scarso P, Limongi F, Iannizzi P, et al. Health related quality of life in adults with repaired tetralogy of Fallot: psychosocial and cognitive outcomes. Heart 2005; 91 (2): 213-218.

3 Intellectual, neuropsychological, and behavioral functioning in children with tetralogy of Fallot 65

3 I n t e l l e c t u a l , n e u r o p s y c h o l o g i c a l , a n d b e h a v i o r a l f u n c t i o n i n g i n c h i l d r e n w i t h t e t r a l o g y o f F a l l o t

Marijke Miatton, Daniël De Wolf, Katrien François, Evert Thiery, Guy Vingerhoets

Journal of Thoracic and Cardiovascular Surgery 2007; 133: 449-455.

A b s tr ac t

Objective: Although it is known that pediatric cardiac surgery holds risks for later development, few studies investigated the long-term development in children with tetralogy of Fallot. The purpose of this study was to define their intellectual capacities, neuropsychological profile, and behavioral functioning, 6 to 12 years postoperatively. Methods: Patients (n= 18, 8y3m ±1y6m) were examined with a short form intelligence scale (WISC-III) and a neuropsychological assessment battery (NEPSY). Their parents completed a behavioral questionnaire. The patient group was compared to an acyanotic congenital heart disease group and to a healthy control group. Results: No significant differences between the patient group and the acyanotic group emerged. Compared to the healthy control group, children with tetralogy of Fallot showed significantly lower scores on the estimated Full Scale IQ (p< .05), and on the NEPSY domains Language (p< .01) and Sensorimotor functioning (p<. 01). Also the subtests ‘tower’ (p< .05), ‘memory for names’ (p< .05), ‘narrative memory’ (p< .05) and ‘design copy’ (p< .05) elicited group differences. Parental reports revealed significantly higher scores on attention problems (p < .05) and the total problem scale (p< .05), as well as significantly lower school performances than these of healthy peers (p< .01). Conclusions: In children with tetralogy of Fallot, we identified a lower estimated full-scale intelligence than in healthy peers and a neuropsychological profile characterized by primarily mild motor deficits and difficulties with language tasks. Parents of the children with tetralogy of Fallot indicated attention problems and rated the child’s school competencies to be lower than in healthy controls.


66 3 Intellectual, neuropsychological, and behavioral functioning in children with tetralogy of Fallot


Tetralogy of Fallot (TOF) is one of the most common forms of cyanotic congenital heart disease (CHD) (1). A cyanotic defect results in abnormal blood flow through the lungs, preventing full oxygenation of the blood and causes symptoms as cyanosis, breathlessness, fatigue and growth retardation (2). Today, these children are operated at an early age, to normalize their cardiopulmonary status as soon as possible. Many studies sought to define differences in functional outcome between cyanotic and acyanotic forms of CHD. In an acyanotic type of CHD, the circulation to the lungs is normal and there is full oxygenation of the systemic blood. Generally, it is postulated that, due to the difference in severity of the symptoms, cyanotic forms of CHD result in lower functional outcome than acyanotic forms of CHD (3). However, this is not always supported by clinical evidence (4, 5). Only a few studies engaged in defining the functional outcome in isolated diagnostic groups. Research on children with transposition of the great arteries (TGA) or TOF, two cyanotic forms of CHD, revealed significantly lower scores on academic skills such as reading, spelling, and arithmetic compared to an acyanotic group (1). Differences between both cyanotic groups, TGA and TOF, could not be found (4). Studies on children with TOF showed normal intellectual functioning (5, 6) but marked motor dysfunctions and higher incidence of language deficits (6). Neuropsychological assessment on adult patients with TOF revealed impairment in executive functioning. These patients also reported lower academic levels, despite having spent more time in school (7). Studies on behavior in isolated groups of children with TOF are rare. Moreover, results on behavioral functioning in children with various CHD are inconsistent. While some studies report the presence of significantly higher behavioral problem scores in the CHD –children (8, 9), other studies conclude that no behavioral problems are present, and sometimes the parents even indicate fewer symptoms than parents of healthy children (1, 10). Obviously, the division between cyanotic and acyanotic forms of CHD elicits conflicting results. As a consequence, research on separate diagnostic groups might result in the specification of functional outcome according to diagnosis. In addition, although cognitive dysfunctions at adult age and school problems have been mentioned, the neuropsychological profile of children with TOF remains unknown. The purpose of this study was to define the intellectual capacities, neuropsychological profile, and behavioral functioning of full time school attending children with TOF, 6 to 12 years postoperatively, in order to identify shortcomings or relative difficulties that can lead to tailored interventional programs. We compared the TOF-children to an acyanotic group and to a healthy control group.



P a t i e n t s a n d M e t h o d s


Patients with various CHD operated at Ghent University Hospital, between 1995 and 1999, with a birth weight > 2000g, without perinatal problems and without non-cardiac malformations or genetic abnormalities (Down syndrome, velocardiofacial syndrome, and Di George syndrome) were contacted and invited to participate in the study. From this total group, we selected the children with TOF (n=29) and matched them to a group of children with an acyanotic CHD. All children with TOF, and acyanotic children showing characteristic features of genetic abnormalities at birth, had a genetic screening (Fluorescence In Situ Hybridization, FISH). After exclusion of children with genetic abnormalities (in the TOF-group 8 children, and no children in the acyanotic CHD group), we contacted 21 patients with TOF. One child could not be included because of a severe hearing disorder; two other parents thought participation would be too time-consuming. We included 18 patients with TOF (10 boys, 8y 3m ± 1y 6m) who underwent an open-heart procedure. The TOF-group was compared to a group of children with acynotic CHD (ventricle septum defect, VSD; atrial septum defect, ASD; aortic stenosis or pulmonic stenosis) and to a healthy control group. Besides age and sex, the groups were matched on education level of both parents and on educational level of the child. Local school boards providing normal full time education were contacted with specific demands to find a child matching the TOF-child on sex, age, and educational level of mother and father. All eligible children were tested at school. The local Ethical Committee approved the study and all parents gave written informed consent. Procedures were in accordance with the recommendations found in the Helsinki Declaration of 1975 (11). Medical and surgical data were collected from the patients’ files.


After parental agreement to participate, the child was invited for an intellectual and neuropsychological assessment of half a day. The child was tested with a short form of the Wechsler Intelligence Scale for Children -3rd edition, Dutch version (WISC-III NL). The short form included the subtests Information, Vocabulary, Picture Completion, and Block Design (12). A deviation IQ was calculated using the procedure suggested by Sattler (13). On subtest level a mean performance of 10 (SD 3) is expected. Mean estimated full scale IQ is 100 (SD 15). The neuropsychological battery consisted of all core subtests of the NEPSY (a developmental neuropsychological assessment). The NEPSY tests the child’s neuropsychological development in 5 functional domains in order to detect subtle deficiencies, within and across these functional domains, which can interfere with



learning in preschool and school-aged children (14). The five domains are Attention and Executive Functioning, Memory, Language, Visual-spatial Skills and Sensorimotor Functioning. A mean performance on the domains is 100 (SD 15). B e h a v i o r a l a s s e s s m e n t

During the assessment of the child, the parents completed a behavioral questionnaire. The Child Behavior Checklist (CBCL) reports on the presence of behavioral, social, and emotional problems in 4 to 18-year old children as reported by their parents. The CBCL contains both competence scales and problem behavior scales. In the competence scales, 27 items ascertain the child’s Activities, Social Involvement, and School Performance. A Composite Scale summarizes the total competence of the child. A t-score <37 reflects maladjusted behavior. In the behavior problem scales, 113 questions have to be rated by the parents on a three-point Likert scale to indicate the frequency of the behavior. The items cluster into eight subscales Withdrawn Behavior, Physical Complaints, Anxious/Depressed Behavior, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, and Aggressive Behavior. The first three scales are grouped into a first global scale, Internalizing Behavior. The last two form a second global scale, Externalizing Behavior. All items grouped together constitute the Total Problem Behavior Scale. For each child t-scores (M=50, SD=10) were calculated. On the subscales, a t-score of > 70 and on the global scales (Internalizing, Externalizing, And Total Problem Behavior) a t-score of > 63 are considered to be indicative for clinical follow-up or treatment (15, 16). S t a t i s t i ca l A n a l y s i s

Statistical analyses were performed using the SPSS for Windows statistical software package (version 12.0). Demographics (age at the moment of testing, sex, and educational level of both parents), medical characteristics (birth weight, Apgar scores, duration of extracorporeal circulation, duration of aortic cross clamp and hypothermia), and outcome measures (IQ, NEPSY, CBCL) were compared between the patient groups and control group by means of Chi-square statistics, Wilcoxon Signed Ranks tests or Kruskal Wallis tests. The term significant was used to indicate purely statistical, not clinical, significance. R e s ul t s


Comparison of the three groups (TOF, acyanotic, healthy control group) shows the lowest weight (p< .05) and length (p< .05) at birth in the TOF-group, and also a



larger part of this group has lower Apgar-scores immediately (p < .001) as well as 10 minutes after birth (p < .001). Not surprisingly, in the TOF-group the most frequent symptom was cyanosis while in the acyanotic group presenting symptoms were various. The larger part of our TOF-group had one single operation (77.8%). The maximum number of operations a child underwent was three. Seven patients had initial shunts. Median age at first operation was significantly lower in the TOF group than in the acyanotic CHD-group (p< .05). All patients were operated on using standard procedures for extracorporeal circulation (ECC) under moderate hypothermia (25°-28°C). Circulatory arrest was not used. The TOF-group underwent significantly longer periods of ECC and aortic cross clamp (p< .01). At the moment of testing all children were considered hemodynamically stable and in good health. Results can be found in Table 1.



Table 1. Demographics and medical variables of the three groups

Group TOF-group (n=18)



p†

Age 8y 3m ± 1y 6m 9y 2m ± 1y 6m 8y 4m ± 1y 6m .470 Sex 10 ♂ 8 ♀ 7 ♂ 10 ♀ 10 ♂ 8 ♀ .827 Birth weight (g) 2853 ± 883 3215 ± 637 3419 ± 511 .026* Birth length (cm) 47.9 ± 3.7 49.2 ± 2.8 50.8 ± 1.8 .014* Apgar immediately after birth

< 4: 33.3% 4 – 7: 0%

7 – 10: 66.7%

< 4: 0% 4 – 7: 0%

7 – 10: 100%

< 4: 0% 4 – 7: 0%

7 – 10: 100%

< .001**

Apgar after 10 min

< 4: 22.2% 4 -7: 0%

7-10: 77.8%

< 4: 0% 4 – 7: 0%

7 – 10: 100%

< 4: 0% 4 – 7: 0%

7 – 10: 100%

< .001**

Symptoms None: 13.3 % Cyanosis: 53.3 %

Heart murmur: 13.4 %

≥2 of these symptoms: 20 %

Shortness of breath: 22.2%

Feeding difficulties: 22.2%

Heart murmur: 11.1%

Upper airway infections: 22.2%

Excessive sweating: 11.1%

≥2 of these symptoms: 11.1%

_ _

Age at first operation

Median age 173 days

Median age 603 days

_ .014*

Duration ECC (min)

89.2 ± 31.9 61.0 ± 33.0 _ .018*

Duration aortic cross clamp (min)

51.6 ± 20.7 29.0 ± 21.3 _ .004*

Hypothermia (°C) 25 28 _ .010*

†Kruskal Wallis test and Wilcoxon Signed Ranks Test for respectively three and two groups, ECC: extracorporeal circulation, level of significance * p< .05, ** p < .001




We could not identify any significant differences between the TOF-group and the acyanotic CHD-group. Children in the TOF-group showed significantly lower scores on the estimated Full Scale IQ (p< .05) than their healthy controls. On the NEPSY domains Language (p< .01) and Sensorimotor functioning (p<. 01) and on the subtests ‘tower’ (p< .05), ‘memory for names’ (p< .05), ‘narrative memory’ p (< .05) and ‘design copy’ (p< .05) group differences became apparent. The small sample of children undergoing multiple operations does not permit statistical analysis, but qualitative analysis of the results does not show obvious differences between the children with one single operation for TOF or multiple operations. Mean performances on IQ and NEPSY can be found in Table 2.

Table 2. Group differences on intellectual and neuropsychological performances

Variable (M ± SD) TOF – group (n =18)


Control group

(n = 18)

p†

Intellectual performances (IQ: 100 ± 15, subtest: 10± 3) Estimated full scale IQ 94.6 ± 14.1 97.5 ± 16.3 106.2 ± 15 .014*

Picture completion 8.4 ± 3.1 8.1 ± 4.1 10.0 ± 4.2 .033* Block Design 9.0 ± 3.0 9.9 ± 3.1 10.3 ± 2.2 .229 Information 10.0 ± 2.9 10.8 ± 2.9 11.6 ± 2.0 .076 Vocabulary 9.7 ± 3.0 9.8 ± 2.0 11.0 ± 2.7 .016*

Neuropsychological performances (domains: 100 ± 15, subtests: 10± 3) Attention and Executive Functioning

112.0 ± 13.5 112.9 ± 7.1 117.0 ± 8.5 .070

Tower 12.6 ± 2.6 13.1 ± 1.9 14.1 ± 2.0 .036* Auditory Attention/ Response Set

12.1 ± 1.3 12.6 ± 1.0 12.1 ± 1.3 .176

Visual Attention 10.0 ± 3.3 9.3 ± 2.5 10.4 ± 2.1 .092 Memory 99.4 ± 13.1 106.3 ± 13.8 103.0 ± 9.5 .246

Memory for Faces 11.0 ± 3.3 9.8 ± 3.6 9.6 ± 2.5 .277 Memory for Names 9.6 ± 3.0 8.4 ± 4.0 11.2 ± 1.8 .022* Narrative Memory 9.1 ± 2.5 11.9 ± 2.9 10.4 ± 1.6 .030*

Language 101.1 ± 12.8 101.9 ± 12.3 115.7 ± 14.8 < .001**

Phonological Processing

11.1 ± 3.1 11.3 ± 3.3 13.4 ± 3.2 .003*

Speeded Naming 9.1 ± 2.3 9.2 ± 2.5 10.9 ± 2.1 .011* Comprehension of instructions

10.6 ± 2.1 10.6 ± 2.2 12.7 ± 2.8 < .001**

Visual-spatial skills 110.6 ± 17.3 117 ± 11.0 124.2 ± 11.6 .058



Design Copy 13.0 ± 3.3 14.9 ± 2.1 15.7 ± 1.8 .031* Arrows 11.0 ± 3.5 10.7 ± 2.2 12.0 ± 2.4 .141

Sensorimotor Functioning 90.9 ± 10.6 86.7 ± 15.2 100.9 ± 10.7 < .001** Fingertapping 9.1 ± 1.3 9.6 ± 1.4 10.4 ± 1.7 .021* Imitating hand positions

9.3 ± 2.8 7.7 ± 2.8 11.8 ± 2.2 < .001**

Visuomotor precision 8.0 ± 2.6 7.3 ± 3.5 9.1 ± 2.7 .022*

†Kruskal Wallis test , level of significance *p < .05, ** p < .01

B e h a v i o r a l a s s e s s m e n t

We could not identify any significant differences between the TOF-group and the acyanotic CHD-group. Parental reports revealed significantly higher scores on attention problems (p < .05) and the total problem scale (p< .05) in the TOF-group compared to their healthy controls. The parents of the children with TOF also rated their child’s school performances to be significantly lower than these of healthy peers (p< .01). The small sample of children undergoing multiple operations does not permit statistical analysis, but qualitative analysis of the results does not show obvious differences between the children with one single operation for TOF or multiple operations. Results on the CBCL can be found in Table 3.



Table 3. Group differences on behavioral functioning (CBCL).

Variable TOF – group (n =18)


Control group(n = 18)

p†

Competence Scales ( M ± SD, t-score < 37: clinically significant score) Activity Scale 47.7 ± 6.6 46.4 ± 9.1 49.0 ± 4.7 .526 Social Scale 48.6 ± 8.1 47.3 ± 8.2 47.7 ± 7.3 .515 School Scale 40.2 ± 7.1 45. 2 ± 8.7 51.1 ± 7.3 < .001**

School results Special education Repeating a school year School problems

insufficient: 5.6 % weak: 16.7 %

average: 61.1 % good: 16.7 %

yes: 5.6 % no: 94.4%

yes: 16.7 % no: 83.3%

yes: 66.7 % no: 33.3 %

insufficient: 0% weak: 12.5 %

average: 31.3% good: 56.3%

yes: 0% no: 100%

yes: 18.8% no: 81.3% yes: 56.3% no: 43.8%

insufficient: 0 % weak: 0 %

average: 27.8 % good: 72.2 %

yes: 0% no: 100 % yes: 5.6 % no: 94.4%

yes: 22.2 % no: 77.8 %

.001**

.268

.022*

Problem Behavior Scales (M ± SD, t-score > 63, for individual scales > 70: clinically significant score) Internalizing Behavior 51.1 ± 11.1 53.0 ± 10.6 48.4 ± 7.1 .051

Withdrawn 54.9 ± 7.5 54.1 ± 5.9 52.1 ± 3.5 .065 Physical Complaints 56.8 ± 9.8 57.1 ± 7.4 51.9 ± 3.1 .109 Anxious/ Depressed 53.7 ± 6.4 55.4 ± 6.8 52.7 ± 4.3 .479

Externalizing Behavior 52.8 ± 10.7 52.6 ± 11.9 49.4 ± 7.6 .137 Delinquent Behaviour

53.5 ± 5.4 54.8 ± 6.8 50.7 ± 2.3 .173

Aggressive Behaviour

56.4 ± 7.4 57.1 ± 9.5 53.4 ± 4.3 .186

Social Problems 53.5 ± 4.1 54.8 ± 6.2 51.3 ± 2.4 .051 Thought Problems 54.9 ± 8.0 53.67 ± 4.7 53.5 ± 6.0 .099 Attention Problems 61.5 ± 9.1 59.9 ± 10.9 53.6 ± 5.1 .003* Total Problem Behavior 56.0 ± 11.7 52.7 ± 14.2 47.6 ± 8.1 .003*

†Kruskal Wallis test , level of significance *p < .05, ** p < .01

D i s c u s s i o n

In this study, we defined the intellectual capacities, the neuropsychological performances, and the behavioral functioning of children with TOF, 6 to 12 years postoperatively. We compared the performances of the children in the TOF-group to those of children with acyanotic CHD and to those of healthy children. We could not identify



differences in functional outcome between the TOF-group and the acyanotic CHD-group. This finding is in accordance with previous studies reporting similar intellectual (5) and neuropsychological functioning in children with cyanotic (TOF, TGA) and acyanotic CHD (VSD) (4). Compared to a group of healthy peers, the children in the TOF-group showed lower intellectual abilities, specifically on the subtests picture completion and vocabulary. However, only 3 children had an IQ < 85, confirming that although the intellectual capacities are lower than in the healthy group, the larger part of the children with TOF has a normal level of intelligence (5, 6). Concerning the neuropsychological profile, we found significant differences between the TOF- group and the healthy group on language and sensorimotor functioning. Language deficits have been identified before in children with cyanotic CHD (10, 17), and in the TOF group higher rates of dysfunction in expressive and receptive language have been diagnosed compared to normative data (6). In our study, the children with TOF had more difficulties particularly with phonological awareness, had slower access to names of color, size, and shape, and lacked the ability to process and respond quickly to verbal instructions of increasing difficulty. These objective measures may be the cause of previously reported lower academic skills such as reading and spelling in children with CHD (1, 3). We also found a group difference on sensorimotor functioning. The children with TOF performed worse than healthy peers on subtests measuring motor speed and the ability to imitate finger and hand positions. In a comparative study on children with an acyanotic form of CHD (VSD) and children with TOF, the latter displayed a higher incidence of gross motor dysfunction (6). In our study however, both the children with TOF and the children with acyanotic CHD specifically show slowness in simple and complex motor movements and an inefficient processing of tactile and kinesthetic information when they have to imitate finger and hand positions. Performances on the subtest tower were lower for the TOF-group, indicating more difficulties in tasks concerning executive functioning, which was also reported in a study on adult patients with TOF (7). The hypothesis of damage in the prefrontal cortex is to be further examined. Although obvious memory problems were not present, children with TOF did show lower scores than their healthy peers on a task measuring narrative memory. Possibly, not the memory aspect caused this lower score, but rather their lack of narrative skills. In a study on narrative discourse in children with a cyanotic form of CHD (TGA), 4 years after surgery, their performance differed in frequency and diversity of narrative elements and in adequacy of the information provided (19). Since the number of narrative elements the child can reproduce constitutes the narrative memory score in the present study, this seems a plausible explanation for the lower scores in our TOF-children. Further, memory for names also appeared worse in children with TOF than in healthy controls. The poor performance may be



related to dysnomic problems and a deficient retrieval of sound-symbol association and spoken-written word connections, which can be reduced to deficient linguistic skills. Visual-spatial skills constituted another domain in which children with TOF performed worse than healthy controls. Their ability to copy two-dimensional geometric figures was reduced. We hypothesize that the lower score on design copy was caused by hand-eye coordination difficulties and visual perceptual deficits, which have been previously reported in children after infant heart surgery (1, 17, and 18). The behavioral functioning of children with TOF in our study group, measured by means of a parental questionnaire, is characterized by mainly attention and school problems. These results contradict the previously reported absence of behavioral problems in children with cyanotic CHD (1, 10). Other studies however, did report a higher incidence of behavioral problems (9), specifically a higher risk for attention problems (20). These attention problems, might have led, at least partially, to the significantly lower school competency in TOF-children, reported by the parents. Specifically, lower school results and more school problems were indicated. This finding is in accordance with follow-up studies in adolescents and adults with CHD that report patients to have spent longer periods in school (21), display more need for special education and more often present with a learning disability (22). Neuropsychological deficits that have been mentioned before in outcome studies (6, 10, and 17) are probably responsible for the shortcomings at school level. The small sample size constitutes a limitation in our study. Further, we can not ignore a possible selection bias in the patient groups. Parents of children with a congenital heart disease voluntarily entered the study. The suspicion of a neurodevelopmental or behavioral problem in their child might have been the parent’s motivation for participation, while parents of children that perform well at school, may have wished not to stigmatize their child as a patient. In accordance with previous studies (23), our data reflected lower birth weight in the TOF-group. However, this birth weight is still within the normal range (2853g). Adverse cognitive outcome has been described in children with very low (<1501g) and extremely low birth weight (≤ 1000g) (24). For this reason, we believe the relatively lower birth weight in the TOF-group was of little influence on the reported neuropsychological outcome. In this outcome study, we compared the intellectual, neuropsychological, and behavioral function of children with TOF, 6 to 12 years postoperatively to a group with acyanotic CHD, and to healthy peers. We could not identify any functional outcome differences between the TOF-group and the acyanotic group. In the TOF-group, we identified a lower estimated full-scale intelligence and a neuropsychological profile characterized by mainly mild motor deficits and



difficulties with language tasks. Attention problems and lower school competencies are the most important behavioral aspects parents of children with TOF reported. In general, our findings are comparable to most outcome studies on children with CHD. However, our study resulted in the identification of specific neuropsychological shortcomings in children with CHD which can lead to tailored interventional programs focused especially on motor functions and language. By means of these programs, the mentioned school problems and the long-term neuropsychological sequelae might be prevented.



R e f e r e n c e s

1. Wright M, Nolan T. Impact of cyanotic heart disease on school performance. Arch Dis Child 1994; 71: 64-70.

2. Wray J, Sensky T. How does the intervention of cardiac surgery affect the self-perception of children with congenital heart disease? Child Care Health Dev 1998; 24 (1): 57-72.

3. Wray J, Sensky T. Congenital heart disease and cardiac surgery in childhood: effects on cognitive function and academic ability. Heart 2001; 85:687-691.

4. Oates R, Simpson J, Cartmill T, Turnbull J. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child 1995; 72: 298-301.

5. Haneda K, Itoh T, Togo T, Ohmi M, Mohri H. Effects of cardiac surgery on intellectual function in infants and children. Cardiovasc Surg 1996; 4 (3): 303-307.

6. Hövels-Gürich H, Konrad K, Skorzenski D, Nacken C, Minkenberg R, Phys D, Messmer B, Seghaye MC. Long-term neurodevelopmental outcome and exercise capacity after corrective surgery for Tetralogy of Fallot or Ventricular Septal Defect in infancy. Ann Thorac Surg 2006; 81: 958-967.

7. Daliento L, Mapelli D, Russo G, Scarso P, Limongi F, Iannizzi P, Melendugno A, Mazzotti E, Volpe B. Health related quality of life in adults with repaired tetralogy of Fallot: psychosocial and cognitive outcomes. Heart 2005; 91: 213-218.

8. Utens E, Verhulst FC, Meijboom FJ, Duivenvoorden HJ, Erdman RA, Bos E, Roelandt JT, Hess J. Behavioural and emotional problems in children and adolescents with congenital heart disease. Psychol Med 1993; 23: 415-424.

9. Oates RK, Turnbull JA, Simpson JM, Cartmill TB. Parent and teacher perceptions of child behaviour following cardiac surgery. Acta Paediatr 1994; 83: 1303-1307.








15. Achenbach TM. Manual for the Child Behaviour Checklist/ 4-18 and 1991 profile. Burlington, VT: University of Vermont, 1991.

16. Verhulst FC, van der Ende J, Koot H M. Handleiding voor de CBCL/ 4-18 [Manual of the CBCL / 4 -18]. Rotterdam, The Netherlands, Universiteit Rotterdam, 1996.


18. Hemphill L, Uccelli P, Winner K, Chang CJ, Bellinger D. Narrative discourse in young children with histories of early corrective heart surgery. J Speech Lang Hear Res 2002; 45 (2): 318-331.

19. Bellinger D, Bernstein J, Kirkwood M, Rappaport L, Newburger J. Visual-Spatial skills in children after open-heart surgery. J Dev Beh Pediatr 2003; 24 (3): 169-179.

20. O’Dougherty M, Berntson G, Boysen S, Wright F, Teske D. Psycho-physiological predictors of attentional dysfunction in children with congenital heart defects. Psychophysiology 1988; 25: 305-315.

21. Ternestedt BM, Wall K, Oddsson H, Riesenfeld T, Groth I, Schollin J. Quality of life 20 and 30 years after surgery in patients operated on for Tetralogy of Fallot and for Atrial Septal Defect. Pediatr Cardiol 2001; 22: 128-132.

22. Nolan T, Pless B. Emotional correlates and consequences of birth defects. J Pediatr 1986; 109, 201-216.

23. Kramer HH, Trampisch HJ, Rammos S, Giese A. Birthweight of children with congenital heart disease. Eur J Paediatr 1990; 149:752-757.



24. Böhm B, Katz-Salamon M, Smedler AC, Lagercrantz H, Forssberg H. Developmental risks and protective factors influencing cognitive outcome at 5 ½ years of age in very-low-birthweight children. Dev Med Child Neurol 2002; 44, 508-516.

4 Medical and surgical predictors of neuropsychological deficits in CHD 81

4 M e d i c a l a n d s u r g i c a l p r e d i c t o r s o f n e u r o p s y c h o l o g i c a l d e f i c i t s i n s c h o o l -a g e d c h i l d r e n w i t h a s u r g i c a l l y c o r r e c t e d c o n g e n i t a l h e a r t d i s e a s e

A b s tr ac t

Although literature on outcome measures in children with congenital heart defects primarily focused on cerebral injury related to cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), the etiology of neurological and neuropsychological deficits is known to be multifactorial with preoperative, peri-operative and postoperative factors contributing to the outcome. In this study, we tried to quantify the additive predictive value of preoperative, peri-operative and postoperative factors. We investigated the possible effect of Apgar immediately after birth and after 10 minutes, duration of ECC and duration of aortic cross clamp, and duration of intubation and duration of stay in ICU on neuropsychological outcome of the child with a congenital heart disease. We could not identify any medical or surgical predictors for the adverse neuropsychological outcome in children with CHD 6 to 12 years postoperatively. The small sample size might have contributed to this lack of predictive value of the selected medical and surgical variables. Nevertheless, the results of this study suggest that surgical variables are not individually responsible for adverse neuropsychological outcome in children with CHD. Rather multiple risk factors should be kept in mind, with possibly different sizes of impact.


82 4 Medical and surgical predictors of neuropsychological deficits in CHD


Although literature on outcome measures in children with congenital heart defects primarily focused on cerebral injury related to cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), the etiology of neurological and neuropsychological deficits is known to be multifactorial with preoperative, peri-operative and postoperative factors contributing to the outcome. Various factors have been revised separately but the cumulative impact of several pre-, peri- and postoperative factors on the neuropsychological functioning of children with surgically corrected CHD still yields conflicting results. In the preoperative stage, neurobehavioral assessments and neurological examination in newborns with congenital heart defects revealed abnormalities in more than half of the cohort (1). It is known that 5 to 8 % of CHDs result from chromosome abnormalities (Down syndrome and 22q11.2 deletions). Since approximately 15 to 20% of all conotruncal cardiac malformations are diagnosed with a 22q11.2 deletion, this genetic syndrome is one of the most common etiologies of heart defects in cardiology (2). Knowing the genetic status of the child is of crucial importance to predict the mid-term neuropsychological outcome as these genetic syndromes in se involve intellectual and neuropsychological deficits as well. Other influencing variables are prematurity and low birth weight, often associated with cognitive deficits (3), and thus best seen as exclusion criteria or entered in the study as confounding variables. The unstable cardiac status of the newborn often requires urgent treatment. Certain heart defects however, are repaired later in life, prolonging the risk for hypoxic events. A significant negative correlation between age of corrective surgery (for cyanotic heart defects) and IQ scores has been obtained, suggesting that longer periods of chronic hypoxia may reduce intelligence (4, 5). Contrasting evidence alternatively stated that for children with TGA or TOF, delaying the operation does not appear to adversely affect their intellectual development (6). Preoperatively, the presence of low arterial oxygen saturation (<85%) and metabolic acidosis (pH< 7.15) signifies low cardiac output, poor tissue perfusion, and increased risk for adverse events (7). Because severe acidosis may exaggerate ischemic, glial, and vascular cell damage, it may also be associated with adverse functional outcome (8). In the peri-operative stage, different cardiopulmonary bypass techniques such as continuous low-flow bypass (LFB) or circulatory arrest (CA) are used, depending on the type of cardiac defect. Several aspects and techniques can influence homeostasis: anesthesia, cooling and rewarming, reduction in pump flow or circulatory arrest, pH management, type of oxygenator, hematocrit of the circuit while on bypass (9). These variables are discussed in the review article (chapter 1). The use of CA under deep hypothermia is associated with significantly lower IQ-scores compared to healthy siblings and to children undergoing LFB under moderate hypothermia. Per



minute of circulatory arrest time a reduction of 0.53 IQ-points was noted (10). Combined CA and low flow bypass in the neonatal arterial switch operation is associated with neurological as well as fine and gross motor impairment but appears to be well tolerated concerning cognitive functions as based on a formal intelligence testing (11). The majority of children with CHD are operated on by means of LFB under moderate hypothermia. Low-flow cardiopulmonary bypass is called superior to CA because it supposedly does not impair cerebral perfusion (12). However, this finding was countered by the Boston Circulatory Arrest study that could not show a significant difference between these support methods on neurological testing 8 years after surgery (13). Studies on the developmental and neurological effects of pH management for deep hypothermic cardiopulmonary bypass have proven children randomized to the pH-stat and α- stat method not to differ significantly at 1 year of age in their scores on the Bayley Infant Scales of Development or in their neurological examination. In addition, at the age of 2 to 4 years both groups of children had similar development as assessed by parental responses (14). Hemodilution during cardiopulmonary bypass was introduced to decrease homologous blood use and was thought to improve microcirculatory flow. Animal models however show that certain protocols for hemodilution during cardiopulmonary bypass might cause brain injury by hypoxic-ischemic injury. To test this hypothesis, a study was set up that randomly assigned children needing reparative cardiac surgery at less than 9 months of age to undergo hemodilution to a hematocrit level of approximately 20% versus 30%. Children assigned to the lower-hematocrit group had worse peri-operative outcome and a lower psychomotor developmental index (PDI). A significantly greater proportion of these children showed PDI scores of more than two SD less than the population mean. Mostly motor deficits were found but other domains, for instance language or visual-motor integration that cannot be easily assessed in 1-year olds, might equally be affected, which leaves the optimum hematocrit level during infant cardiac surgery to be refined (15). Finally, important postoperative factors such as hemodynamic stability after the operation, length of stay in the intensive care unit, and the possible need for multiple operations can also significantly influence the long-term outcome of the child. Logically, the risk for neuropsychological consequences increases after successive operations. It has been shown that children that undergo multiple operations, for instance in the case of hypoplastic left heart syndrome, had somewhat lower IQ-scores than expected (16). However, the need for multiple operations also reflects the severity of the CHD and is thus an influencing variable on IQ in the study mentioned. The postoperative healing process of the child is reflected in the length of stay in the cardiac intensive care unit (CICU) and is a marker for various events as hypotension



or hypoxia, which can culminate in adverse cognitive outcome. Longer postoperative stay in CICU was indeed associated with worse cognitive functioning in 8-year old children (17). In infants with critical CHD who need open hart surgery approximately 4 to 10% experience early transient postoperative clinical seizures. Using continuous EEG-monitoring an even higher incidence of children with seizure activity is detected. Postoperative clinical and EEG seizures are associated with worse neurodevelopmental outcomes at ages 1 year and 2 ½ years in children with TGA (18). Identifying surgical and/or medical markers of adverse neuropsychological outcome will define a high-risk group that, in future, can be targeted for early intervention, and that will permit the cardiologist or cardiac surgeon to give accurate information to the parents concerning the postoperative functional outcome of their child. Therefore, the objective of this study was to explore pre-, peri- and postoperative outcome predictors of neuropsychological deficits in school-aged children with a surgically corrected congenital heart disease (CHD). M e t h o d

P a t i e n t ch a r a c t e r i s t i cs , m e d i ca l a n d s u r g i ca l d a t a

Patients with various congenital heart diseases, operated in the Ghent University Hospital, between 1995 and 1999, with a birth weight > 2000g, without perinatal problems, and without non-cardiac malformations or genetic abnormalities (Down syndrome, Velocardiofacial syndrome, and Di George) were contacted and invited to participate in an outcome study. All children with tetralogy of Fallot (TOF) and all other children showing characteristic features of genetic abnormalities at birth had a genetic screening (Fluorescence In Situ Hybridization, FISH) to exclude for Di George/Velocardiofacial syndrome. In total, 43 patients that underwent an open-heart procedure were included in the project (21 girls, 22 boys). The mean time between operation and testing was 8y 2 m ± 1y 10m (range 5y 3m – 10y 8m). Medical and surgical data were collected from the patient’s files. We included birth weight and length, Apgar score immediately after birth and after 10 minutes, diagnosis, arterial oxygen saturation pre-and postoperatively, presence of metabolic acidosis pre-and postoperatively, number of catheterizations, number of operations, duration of the operation(s), degree of hypothermia, duration of the extracorporeal circulation (ECC), duration of aortic cross clamp, duration of the stay in the Intensive Care Unit, duration of intubation, postoperative clinical and/or EEG-recorded seizures. Because all children were operated on by means of low-flow bypass under moderate hypothermia and no child in our study sample experienced clinical or EEG-recorded seizures, these two variables (degree of hypothermia and clinical and/or EEG seizures) were not used in further analyses.




After agreeing to participate, children were invited for a neuropsychological assessment of 2 to 3 hours duration. The child was tested with a short form of the Wechsler Intelligence Scale for Children-3rd edition, Dutch version (WISC-3rd NL). The neuropsychological battery consisted of all core subtests of the NEPSY (a developmental neuropsychological assessment), measuring five functional domains: attention and executive functioning, memory, language, visual-spatial skills and sensorimotor functioning (19). S t a t i s ti c s

Statistical analyses were performed using the SPSS for Windows statistical software package (version 12.0). To reduce the number of predictors we made a selection based on high correlations between certain variables (Apgar immediately after birth and after 10 minutes, duration of ECC and duration of aortic cross clamp, and duration of intubation and duration of stay in ICU). We used nonparametric logistic regression analyses with Estimated Full Scale IQ and the NEPSY domains as dependent variable and Apgar after birth, arterial oxygen saturation pre-and postoperatively, presence of metabolic acidosis pre-and postoperatively, number of catheterizations, number of operations, duration of ECC, and duration of stay in ICU as independent variables. To increase the sensitivity of our statistical analyses, we also applied parametric stepwise linear regression analyses. R e s ul t s

P a t i e n t ch a r a c t e r i s t i cs , m e d i ca l a n d s u r g i ca l d a t a

The mean age at testing of the total CHD-group was 8y8m ± 1y6m. We divided the CHD-group in a cyanotic and an acyanotic CHD-group. The patient group consisted of 43 patients with various congenital heart defects: transposition of the great arteries (TGA) (n = 5), tetralogy of Fallot (TOF) with or without ASD type II (n = 18), totally anomalous pulmonary venous connection (n = 1), truncus arteriosus (n = 2), atrial septal defect (ASD) (n=9), ventricular septal defect (VSD) (n=6), pulmonic stenosis (n=1), and aortic stenosis (n=1). The children presented with two or more of the following symptoms: cardiac defect/ heart murmur, blue skin/lips, recurrent upper airway infections, shortness of breath, feeding difficulties or sweating. All children underwent an open-heart operation with full flow cardiopulmonary bypass under moderate hypothermia (25°C-33°C). No child had experienced clinical or EEG recorded seizures. Medical data can be found in Table 1.

Table 1. Medical characteristics



Medical data Patient group (n= 43) M ± SD

Preoperative characteristics Birth weight Birth length Apgar score immediately after birth Apgar score after 10 minutes

3094 ± 741 48.9 ± 3.1

< 4: 15.8% 4-7: 0% 7-10: 84.2% < 4: 10.5% 4-7: 0 % 7-10: 89.5 %

Surgical data Number of catheterizations Number of operations Duration of the ECC (min) Duration of the aortic cross clamp (min)

0: 67.4% 1: 27.9% 2: 4.7% 1: 81.4% 2: 14.0% 3: 4.7%

84 ± 33 46 ± 23

Postoperative outcome Duration of the stay in ICU Duration of intubation

≤1 day: 33.3% 2-4 days: 52.4%

≥5days:14.4% ≤1 day: 71.4% 2-4 days: 16.7%

≥5days: 12% N e u r o p s y c h o l o g i c a l a s s e s s m e n t

On the short form intelligence scale, we found a significantly lower Estimated Full Scale IQ for the total CHD-group (p<.01). Two of the subtests included were significantly lower in the patient group: Picture Completion (p<.01) and Vocabulary (p<.05). Children with CHD performed significantly lower on the domains of Sensorimotor Functioning (p<.001) and Language than healthy controls. Each subtest included in both domains yielded significantly lower results. Attention and Executive functioning (p< .05) as well as Memory (p<.05) also displayed significantly lower performances in the CHD-group. Visual-spatial skills did not elicit group differences. Despite these differences between both groups, neither with nonparametric, nor with parametric statistical analyses could we identify any medical or surgical predictors for the adverse neuropsychological outcome in children with CHD, described in chapter 2. D i s c u s s i o n

At first, most studies attributed neurodevelopmental sequelae in children with CHD mainly to surgical procedures, but the etiology appeared multifactorial with preoperative, peri-operative and postoperative factors contributing to the outcome. In this study, we tried to quantify the additive predictive value of preoperative, peri-operative and postoperative factors. However, we could not identify any medical or surgical predictors for the adverse neuropsychological outcome in children with



CHD 6 to 12 years postoperatively, as described in chapter 2. The small sample size might have contributed to this lack of predictive value of the selected medical and surgical variables. Nevertheless, the results of this study suggest that surgical variables are not individually responsible for adverse neuropsychological outcome in children with CHD. Rather multiple risk factors should be kept in mind, with possibly different sizes of impact. Different risk factors might have contributed to the neuropsychological outcome of children with CHD and undoubtedly, certain risk factors were not included. For instance, obvious dysmorfic features at birth are reason for genetic screening. Not every child in our sample size received genetic screening so we cannot be certain that our study group was entirely free of genetic abnormalities. Further, structural brain imaging is not part of the standard examination protocol in children with CHD, nor is a neurological examination. It is thus impossible to rate the impact of the preoperative cerebral and neurological status of the children in our group on the mid-term neuropsychological outcome. In addition, contemporary research names polymorphisms of apolipoprotein E as a risk factor for worse neurological outcome after central nervous system injury. Results show a significant effect of the APOE є2 allele to predict lower psychomotor developmental index at 1 year of age after cardiac surgery (20), indicating a genetic predisposition to adverse outcome. Despite the usefulness of the search for predictors of adverse outcome, it should not be forgotten that the larger part of children with CHD displays a normal neurocognitive development. Since these children are operated on at early age, plasticity of the brain can play an important role in the reorganization of the brain or compensation by other brain regions after possibly occurred damage. This brain plasticity might be, at least partially, responsible for the normal neurodevelopmental status of the larger part of children with CHD. Future studies should strive for the identification of demographic, medical, preoperative, peri-operative, and postoperative predictors of adverse neuropsychological outcome in children with CHD in order to provide accurate and reliable information to the parents concerning the postoperative functional outcome of their child.



R e f e r e n c e s

1. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurologic status of newborns with congenital heart defects before open-heart surgery. Pediatrics 1999; 103 (2): 402-408.

2. Colemann K. Genetic counselling in congenital heart disease. Crit Care Nurs Q 2002; 25 (3): 8-16.

3. Böhm B, Katz-Salamon M, Smedler AC, Lagercrantz H, Forssberg H. Developmental risks and protective factors influencing cognitive outcome at 5 ½ years of age in very-low-birthweight children. Dev Med Child Neurol 2002; 44, 508-516.

4. O’Dougherty M, Wright FS, Garmezy N, Lowenson RB, Torres F. Later competence and adaptation in infants who survive severe heart defects. Child Development 1983; 54: 1129-1142.

5. O’Dougherty M, Wright FS, Loewenson RB, Torres F. Cerebral dysfunction after chronic hypoxia in children. Neurology 1985; 35: 42-46.

6. Oates RK, Simpson JM, Cartmill TB, Turnbull JAB. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child 1995; 72 (4): 298-301.

7. Hatherill M, Salie S, Waggie Z, Lawrenson J, Hewitson J, Reynolds L, et al. Hyperchloraemic metabolic acidosis following open cardiac surgery. Arch Dis Child 2005; 90: 1288-1292.

8. Verheijen P, Lisowski L, Stoutenbeek P, Hitchock J, Brenner J, Copel J. Prenatal diagnosis of congenital heart disease affects preoperative acidosis in the newborn patient. J Thorac Cardiovasc Surg 2001; 121: 798-803.

9. Kirkham FJ. Recognition and prevention of neurological complications in pediatric cardiac surgery. Pediatr Cardiol 1998; 19: 331-345.

10. Wells FC, Coghill S, Caplan HL, Lincoln C, Kirklin JW. Duration of cardiopulmonary arrest does influence the psychological development of children after cardiac operation in early life. J Thorac Cardiovasc Surg 1983; 86: 823-831.

11. Hövels-Gürich HH, Seghaye MC, Däbritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114 (4): 578-585.



12. Scallan MJH. Brain injury in children with congenital heart disease. Pediatric Anesth 2003; 13: 284-293.

13. Ungerleider, R.M., Gaynor, J.W. The Boston Circulatory Arrest Study: An analysis. J Thoracic Cardiovasc Surg 2004; 127: 1256-61.

14. Bellinger DC,Wypij D, du Plessis AJ, Rappaport LA, Riviello J, Jonas RJ, et al.. Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 2001; 121 (2): 374-383.

15. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ et al. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003; 126: 1765-1774.

16. Uzark K, Lincoln A, Lamberti JJ, Mainwaring RD, Spicer RL, Moore JW. Neurodevelopmental outcomes in children with Fontan repair of functional single ventricle. Pediatrics 1998; 101 (4): 630-633.

17. Newburger JW, Wypij D, Bellinger DC, du Plessis AJ, Kuban KCK, Rappaport LA et al. Length of stay after infant heart surgery is related to cognitive outcome at age 8 years. J Pediatr 2003; 143: 67-73.

18. Rappaport LA, Wypij D, Bellinger DC, Helmers SL, Holmes GL, Barnes PD, et al. Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Circulation 1998; 97: 773 – 779.

19. Korkman, M., Kirk, U., Kemp, S. (1998). NEPSY. A developmental neuropsychological assessment. The Psychological Corporation. A Harcourt Assessment Company.

20. Gaynor JW, Gerdes M, Zackai EH, Bernbaum J, Wernovsky G, Clancy RR, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thoracic Cardiovasc Surg 2003; 126: 1736-1745.

5 Behavior and self-perception in children with a surgically corrected congenital heart disease 91

5 B e h a v i o r a n d s e l f - p e r c e p t i o n i n c h i l d r e n w i t h a s u r g i c a l l y c o r r e c t e d c o n g e n i t a l h e a r t d i s e a s e


Journal of Developmental and Behavioral Pediatrics, in press

A b s tr ac t

We sought to combine parental and child reports in order to describe the behavior, self-perception, and emotional profile of children with a surgically corrected congenital heart disease (CHD). Forty-three children with a surgically corrected CHD were selected and compared to an age- and sex matched healthy group. The parents of the CHD-children completed a behavior rating scale, the Child Behavior Checklist. Children ≥ 8 years (n=23) completed a self-report questionnaire concerning perceived competence, their anxiety level and feelings of depression. As opposed to parents of healthy children, those of CHD-children report significantly lower school results (p<. 01), more school problems in general (p<. 01), and a higher percentage of their children repeated a school year (p<. 01). They also reported more social (p<. 01) and attention problems (p<. 01), and more aggressive behavior (p< .05). On self-perception and state anxiety questionnaires, no significant differences were found between the patient group and the healthy group. On a depression scale however, children with a surgically corrected CHD reported more depressive feelings than healthy controls (p<. 01).


92 5 Behavior and self-perception in children with a surgically corrected congenital heart disease


Follow-up studies of children that underwent surgical correction for congenital heart disease (CHD) revealed good anatomical results and increased life expectancy (1). Despite the higher incidence of psycho-emotional disturbances in school-aged children with chronic illness than in healthy children (2, 3), few studies have investigated psychosocial outcome and quality of life in CHD-children. Research on an adolescent and adult patient group revealed the need for special education at school age and a high incidence of learning disorder or mental retardation (4). Investigators therefore shifted their focus to the behavioral and emotional functioning at school age, and at first, parents were addressed as the main source of information. Dependent on the type and severity of CHD, parents reported various behavioral and emotional problems. In children with transposition of the great arteries, psychological outcome studies showed significant psychological symptoms such as separation anxiety disorder, social phobia, dysthymic disorder (chronic state of depression), and oppositional defiant disorder (pattern of hostile, negative and defiant behavior) (5). Parents of children with univentricular hearts described their children as more withdrawn, having more social problems and engaging in fewer activities (6). Even in children who underwent total repair of their CHD, parents still reported significantly higher behavioral problem scores than normative reference groups 9 years after the operation (7, 8). Their participation in school and/or leisure sports however was good, and the level of physical activity was rated equal to that of healthy mates (9). Only a few studies utilized the children’s self-reports. Children with totally corrected CHD did not rate their quality of life and self-perception to be different to that of healthy peers (6, 10, and 11). Some studies however, including children with various CHD found reduced self- reported motor functioning and autonomy compared to healthy children (12). The presence of medical fears and symptoms of physiological anxiety have also been shown (13). A comparative study on the self-perception in children with various CHD (aged 5 to 15 years), children awaiting bone marrow transplantation, and healthy children revealed CHD-children to rate themselves as weaker, more frightened, and more ill than the healthy group, and even weaker than the group of children awaiting bone marrow transplantation (14). A more recent study confirmed this significantly lower physical self-concept in CHD-children as opposed to healthy children, but found no group differences in family, school, appearance, and emotional and general self-concept (15). Although these studies resolved many challenges, they do contain some limitations. The medical and surgical treatments used in adolescent and adult patient samples are different from the techniques used at present. In the late 1990’s, new perfusion techniques were developed in order to minimize or avoid the use of deep hypothermic circulatory arrest (16), which was associated with significant late



morbidity in a large percentage of children (17). Therefore, the results of older studies might not be applicable to the present generation of children operated for congenital heart disease. We chose a young age group in order to present data on the quality of life in children with CHD operated on by means of contemporary techniques. This way, we can estimate if improved medical treatment has led to improved patient perceptions. Additionally, most research primarily utilized parental reports on the child’s well being while, to our knowledge, only a few studies have used self-reports in a younger age group. Further, although neurological outcome studies frequently report the presence of motor dysfunction (18, 19) in CHD-children, few studies questioned the child about his or her perceived competence on this domain. Most studies also failed to include a healthy control group and merely compared the ratings of the child with normative data. In this study, we chose to combine parental reports on behavior with self-reports of 8 to 12-year old children with CHD on perceived competence in several domains including motor functioning, feelings of depression and anxiety. The results were compared to a healthy control group. Because we sought to define the behavior and self-perception of those CHD-children that were considered to function normally in daily life, all children included in our study group were full-time school attendees. M e t h o ds


This study is part of a follow-up study on neuropsychological and behavioral outcome in children with surgically corrected congenital heart disease. Patients with various congenital heart diseases, operated at the Ghent University Hospital Belgium, between 1995 and 1999, with a birth weight > 2000g, without perinatal problems and without non-cardiac malformations were contacted and invited to participate in the study (n = 163). Several candidates had moved and could not be traced (n = 17). Various reasons were given by non participators: presence of a developmental disorder (n= 2, one boy with autism, one boy with a severe learning disorder), testing being too time consuming (n= 27), awaiting new cardiac surgery for the child (n = 2), not wanting to confront the child with something that happened a long time ago (n = 19), stating that the child has no cognitive problems and participating would imply that he or she does (n = 8). Reason for not participating remained unclear in 31 cases that did not respond in any way to the invitation. All children with TOF (tetralogy of Fallot) and all other children showing characteristic features of genetic abnormalities at birth had a genetic screening (Fluorescence In Situ Hybridization, FISH) to exclude for genetic syndromes such as Down syndrome or Di George/Velocardiofacial syndrome. In total, 57 patients were included in the



project of which we selected only those patients that underwent an open-heart procedure (n=43; 21 girls, 22 boys). Besides age and sex, the groups were matched on education level of both parents and on educational level of the child. Local school boards providing normal full time education were contacted with specific demands to find a child matching the CHD-child on sex, age, and educational level of mother and father. All eligible children were tested at school. All patients underwent an open-heart operation with full flow cardiopulmonary bypass under moderate hypothermia (25°C-33°C). The median age at operation was 2 months. While the New York Heart Association Class (NYHA-class) and the Child Behavior Checklist (CBCL) can be used in a broad age range of 4 to 18 years, the self-report questionnaires were only completed by children ≥ 8 years. The local Ethical Committee approved the study, and all parents gave written informed consent. Procedures were in accordance with the recommendations found in the Helsinki Declaration of 1975 (20). B e h a v i o r a l a s s e s s m e n t

P a r e n t a l r e p o r t s

Parents were asked to complete the following questionnaires. - N e w Y o r k H e a r t A s s o c i a t i o n C l a s s – m o d i f i e d ( N Y H A - c l a s s )

The New York Heart Association Class classifies the functional status of the child (21). The classes are summarized in Table 1.



Table 1. Symptom score: Modification of New York Heart Association Class for use in

children

Class I Cardiac disease with no limitation of physical activity. School-aged child takes gym class and keeps up with peers.

Class II Slight limitation of physical activity. Comfortable at rest, but ordinary activity can cause fatigue, palpitations, or dyspnea. School-aged child takes gym class but does not keep up with peers. Secondary growth failure is likely.

Class III Marked or severe limitation of physical activity. Less than ordinary activity, such as walking less than one block, can cause fatigue, palpitations, or dyspnea. School-aged child is unable to take gym class. Secondary growth failure is likely.

Class IV Unable to perform any physical activity without discomfort. Symptoms are present at rest and increase with any activity. Secondary growth failure is likely.

- T h e A c h e n b a c h C h i l d B e h a v i o r C h e c k l i s t ( C B C L )

This checklist reports on the presence of behavioral, social, and emotional problems in 4 to 18-year old children as reported by their parents. The CBCL contains both competence scales and problem behavior scales. In the competence scales, 27 items inquire about the child’s Activities, Social Involvement, and School Performance. A Composite Scale summarizes the total competence of the child. A t-score <37 reflects maladjusted behavior. In the behavior problem scales, 113 questions have to be rated by the parents on a three-point Likert scale to indicate the frequency of the behavior. The items cluster into eight subscales named Withdrawn Behavior, Physical Complaints, Anxious/Depressed Behavior, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, and Aggressive Behavior. The first three subscales are grouped into a first global scale, Internalizing Behavior. The last two subscales form a second global scale, Externalizing Behavior. All items grouped together constitute the Total Problem Behavior Scale. For each child t-scores (M=50, SD=10) were calculated. On the subscales, a t-score of > 70 and on the global scales (Internalizing, Externalizing, And Total Problem Behavior) a t-score of > 63 are considered indicative for clinical follow-up or treatment (22, 23).



C h i l d r e p o r t

- S e l f - p e r c e p t i o n p r o f i l e f o r C h i l d r e n ( S P P - C )

This scale measures self-concept in 8 to 12-year old children. The 36 items cluster into six subscales that assess perceived competence in School Performance, Social Acceptance, Athletic Activities, Physical Appearance, Behavior, and Global Self-worth. Percentiles ≤ 15 are considered deviant (24, 25). The children completed a supplementary Perceived Motor Competence Scale, measuring both their impression of their motor skills and the importance of motor functions in daily life (26). A score below percentile 15 means the child perceives its own qualities on that specific domain (sports, school …) as very weak. - C h i l d r e n ’ s D e p r e s s i o n I n v e n t o r y ( C D I )

This 27-item questionnaire indicates the presence and severity of a depression in 8 to 17-year old children (27, 28). Scores at percentile 90 or higher, indicate the presence of a depression. - T h e S t a t e - T r a i t A n x i e t y I n v e n t o r y f o r C h i l d r e n ( S T A I - C )

This self-report inventory identifies state anxiety in 8 to 15-year old children and contains 20 sentences referring to vegetative and cognitive symptoms of anxiety present at that moment (29, 30). S t a t i s ti c s

Statistical analyses were performed using the SPSS for Windows statistical software package (version 12.0). Demographics (age at the moment of testing, sex, and educational level of both parents), medical characteristics (weight and length at birth, and Apgar scores) and outcome measures (behavioral assessment) were compared between the patient group and control group. Nominal data were analyzed with Chi-square statistics. Normality was checked by Kolmogorov-Smirnov tests. If the data were not normally distributed, the non-parametric Mann-Whitney U test or Wilcoxon Signed Ranks test was used. For normally distributed data, a MANOVA was used with group (patient or control) as a between subject factor, percentiles of SPP-C scales, deciles of motor competence, deciles of importance of motor function and the percentile of CDI as dependent variables. The term significant indicates purely statistical, not clinical, significance. The level of significance was set at p<. 05. R e s ul t s


The mean age at testing of the total patient group was 8y8m ±1y6m. Because of careful matching, no significant differences between both groups on sex, age, and



maternal educational level were found. Fathers in the control group were slightly higher educated. Demographics can be found in Table 2.

Table 2. Demographics on the patient and the control group

Variable Patient group

n=43 Control group

n=43 F¥ p

Age 8y8m ± 1y6m 8y11m± 1y7m .644 .829

Sex 22 ♂ 21♀ 22 ♂ 21 ♀ .047 † .571

Education father (years)

12.9 ± 2.0 14.3 ± 3.4 4.86 .031*


13.0 ± 1.9 13.7 ± 2.9 1.70 .197

¥ : degrees of freedom [1, 81] , †: χ² value *p< .05

Medical and surgical data were collected from the cardiological and surgical patients’ files. The patient group suffered from various congenital heart defects: transposition of the great arteries (TGA) (n = 5), tetralogy of Fallot (TOF) with or without ASD type II (n = 18), totally anomalous pulmonary venous connection (n = 1), truncus arteriosus (n = 2), atrial septal defect (ASD) (n=9), ventricular septal defect (VSD) (n=6), pulmonic stenosis (n=1) and aortic stenosis (n=1). There was no difference in weight but a significant difference in length at birth (p<.05) between the patient group and the control group. Description of the medical and surgical characteristics of the patient and control group is summarized in Table 3.

Table 3. Medical and surgical characteristics of the patient and control group



p†

Sex 22 ♂ 21 ♀ 22 ♂ 21 ♀ .829‡

Birth weight (g) 3094 ± 741 3385 ± 600 .060

Birth length (cm) 48.9 ± 3.1 50.4± 2.4 .019*


< 4: 15.8%

4 – 7: 0%

7 –10: 84.2%

< 4: 6.5%

4 – 7: 0%

7 – 10: 93.5%

.059¥

Apgar after 10 min < 4: 10.5 %

4 -7: 0%

7-10: 89.5 %

< 4: 0%

4 – 7: 3.2 %

7 – 10: 96.8%

.157¥





p†

Median age at operation 2 months

(range 2 days- 12

months)

_ _

New York Heart Association Class for children

Class I: 83.8 %

Class II: 16.2 %

_ _

†: degrees of freedom =1, level of significance *p< .05, ‡: χ² test, ¥: Wilcoxon signed-rank test

B e h a v i o r a l a s s e s s m e n t

P a r e n t a l r e p o r t

In 83.8% of the CHD-children, parents rated the New York Heart Association Class to be class I. The other 16.2% were rated class II. No classes III or IV were attributed in the patient group. Results on the New York Heart Association Classes can be found in Table 3. Parental report further reveals significantly lower scores for the patient group on School Competence (p<. 001). Parents of CHD-children rate the school results to be significantly lower compared to the healthy group (p<. 01), significantly more children from the patient group repeated a school year (p<. 01) or had more school problems according to their parents (p<. 001). The problem behavior scales Social Problems (p<. 01), Attention Problems (p<. 001), and Aggressive Behavior (p<. 05) appear more frequently in the patient group than in the control group. The Total Problem Behavior score is significantly higher in the patient group (p<. 01). Results on the Child Behavior Checklist results can be found in Table 4.



Table 4. Results on the Child Behavior Checklist (CBCL)

Patient group

n=43 Control group

n=43 Z /F [df]

p

M ± SD

Frequency

< 37 M ± SD Frequency

< 37

Activity 47.9 ± 7.6 12 % 49.0 ± 6.9 13.5 % -0.6 .537

Social 47.5 ± 8.4 21.6 % 48.2 ± 7.2 8.1 % -0.2 .987

School 42.7 ± 8.3 51.2 ± 5.7 -4.0 <.001**

Results insufficient: 3 % weak: 16.2 %

average: 43.2 % good: 37.8 %

insufficient: 0 % weak: 2.7 % average: 27 % good: 70.3 %

-2.8 ¥

.005**

Special Education

yes: 2.7 % no: 97.3 %

yes: 0 % no: 100 %

740† .342

Repeating a school year

yes: 18.9 % no: 81.1 %

yes: 0 % no: 100 %

-2.6† .008**

School problems

yes: 59.5 % no: 40.5 %

21.6 %

yes: 21.6 % no: 78.4 %

2.7 %

-3.3† .001**

Total Competence

47.0 ± 11.8 21.6 % 51.6 ± 9.5 8.1 % -1.7

.091



Patient group

n=43 Control group

n=43 Z /F [df]

p

Problem Behavior Scales M ± SD

Frequency (%) > 70

M ± SD Frequency (%) > 70

Withdrawn Physical complaints Anxious/ Depressed Social problems Thought problems Attention problems Delinquent behavior Aggressive behavior

54.3 ± 6.4

57.0 ± 8.8

54.7 ± 6.4

55.7 ± 6.4

53.9 ± 6.1

61.5 ± 10.2

54.0 ± 5.8

56.5 ± 8.4

4.8 %

9.7 %

2.4 %

2.4 %

7.3 %

31.6 %

4.8 %

12 %

52.0 ± 5.9

53.5 ± 5.6

52.9 ± 4.4

52.0 ± 3.6

52.3 ± 5.0

54.1 ± 5.1

52.1 ± 3.7

53.2 ± 4.4

2.6 %

2.6 %

0 %

0 %

0 %

0 %

0 %

0 %

-1.9

-1.9

-1.4

-2.7

-1.8

-3.4

-1.1

-2.1

.060

.058

.163

.008**

.078

.001**

.262

.037* Total Scores

M ± SD

Frequency (%) > 63

M ± SD Frequency (%) > 63

Internalizing Externalizing Total Problem Score

52.3 ±10.0 52.8 ± 10.9

55.5 ± 11.2

14.5 % 16.9 %

26.7 %

48.0 ± 7.6 49.0 ± 8.5

48.5 ± 9.5

5.2 % 7.8 %

5.2 %

-1.8 -1.5

-2.8

.075

.127

.005**

*p< .05, ** p< .01, ¥: Wilcoxon Signed Ranks Test, †: Mann-Whithney U-Test

C h i l d r e p o r t

The results of the Self Perception Profile for Children (with addition of the ‘Perceived Motor Competence Scale’), the Children’s Depression Inventory and State-Trait Anxiety Inventory, completed by children ≥ 8 years reveal a significantly higher percentile value on the Children’s Depression Inventory in the patient group. No other differences emerged. The results on the self-report questionnaires are summarized in Table 5.



Table 5. Results on the self-report questionnaires of the group ≥ 8 years

Variable (Clinical value)

Patient group n=23

Control group n=23

Z/ F [df] p

Percentiles

Self Perception Profile for Children (pc≤ 15) Scholar competence Social acceptance Athletic skills Physical appearance Behavior Self worth Motor competence (deciles) Importance of motor functions (raw score)

50 47 46 58 63 75 5

2

65 61 54 54 65 82 5

2.5

2.63 [1] 2.70 [1] .82 [1] .20 [1] .07 [1]

1.07 [1] .38 [1]

2.85 [1]

.113

.109

.370

.654

.794

.307

.543

.100

Children’s Depression Inventory (pc > 90) Depression

56

31

8.24 [1]

.007**

Deciles State-Trait Anxiety Inventory for Children (decile > 5 or 6) State anxiety

4

3

-.541¥

.588

¥: Wilcoxon Signed Ranks Test, *: p < .01

D i s c u s s i o n

In this study, we questioned, in a standardized manner, both parents and children with a surgically corrected congenital heart defect on the competence and behavior of the child, 6 to 12 years postoperatively. Parental reports revealed no differences between the patient group and the control group concerning participation in activities and social skills. However, the parents found their children to be significantly less competent in school skills than healthy control children. They also reported lower school results and more school problems in general. Additionally, a higher percentage of CHD-children had repeated a school year. These results are in accordance with previous follow-up studies in adolescents and adults that report



patients to have spent longer periods in school (32), display more need for special education and more often present with a learning disorder (4). On the problem behavior scales, parents of CHD-children judged them to have more social problems, more attention problems and to display more aggressive behavior than children from the healthy control group. Social problems (5) and defiant behavior (6) as well as a higher risk for attention problems (32), have been reported before in CHD-children. Although parents thought their child engaged sufficiently in social activities, they reported problems concerning being teased and not being accepted by peers. Possibly, these social problems elicited the aggressive behavior parents report in their CHD-child. On the cognitive level, parents noticed attention problems. These are confirmed in broader neuropsychological outcome studies. Motor and language difficulties, memory and attention problems and deficits in executive functioning also appeared in this group (9, 11, 14, and 32). These neuropsychological failings were probably and at least partially responsible for the shortcomings at school level. Although the children in our study group were operated by means of new perfusion techniques, avoiding the use of circulatory arrest and therefore adverse neurodevelopmental outcome, parents still report lower school results and school problems in general. The benefits of these newer perfusion techniques on neuropsychological and developmental outcome remain to be examined. The children’s self reports on perceived competence at school, social acceptance, athletic skills, physical appearance, behavior, and self-esteem, did not elicit significant differences compared to the ratings of the healthy children. Specifically, although many studies have proved motor deficits to be common in this group (18, 19), the children themselves rated their motor competences equal to those of healthy peers, and estimated motor functioning equally important in daily life. These results confirm other studies that did not find differences in self-perception and quality of life of children with a surgically corrected congenital heart disease compared to healthy peers (10, 11). However, we could not confirm the previously reported self-perception of reduced motor functioning and reduced autonomy (12). A plausible explanation might be the transitional state these children find themselves in. The worst period of surgical procedures and frequent hospitalizations has passed and future issues such as recurring cardiac symptoms or threatened life expectancy are not yet a concern. Indeed, self-perception has been previously related to the time since diagnosis. The longer the duration, the more negative the ratings are on self-perception (33). Therefore, the moment of assessment of self-perception appears to influence the outcome, which in our case might have caused the positive self-perception ratings. However, we cannot ignore the possibility that these children are actually doing as well as they report. Although anxiety and depression are more frequent in a pediatric cardiac population (5, 14, 34), our results only support the presence of depressive symptoms. Frequent



hospital visits and sometimes not being able to fully participate in sport and social activities restrains the social involvement and acceptance by peers, which might be a reason for a dysthymic state. Indeed, parents of CHD-children did report more social problems such as not being accepted by peers and even being teased or being too dependent from others. The discrepancy between wanting to participate and on the other hand not being accepted by peers in social situations might have caused the slightly elevated depressive states in the CHD-children. Overall, while parents of CHD-children reported more behavioral and especially school problems, the children themselves did not indicate lower perceived competence on school skills or any other skill included. Conflicting results between parental and child reports have been documented before (11, 35). This difference might reflect the tendency of parents to be overprotective and overly concerned about the physical and psychological status of their child. Parental reactions to an acute, life-threatening illness in a child that may have long-term psychologically deleterious effects on both parents and children, has been recognized as a clinical entity called the vulnerable child syndrome (36). Further, previous studies have reported later adjustment of the child with CHD to depend on several factors including emotional state of the parents (7) and parental attitude such as pampering and being overprotective (10). Perhaps more than any other chronic disease, congenital heart disease has the potential for creating psychological maladjustment due to the emotional significance attached to the heart (14). Since we did not include parenting style, or measures that might indicate the presence of the vulnerable child syndrome (such as The Vulnerable Child Scale), we can only speculate on the presence of this syndrome and on the possibility that parental perceptions have led to the reported results. A meta-analysis (2) on a variety of chronic diseases revealed general adjustment problems, internalizing and externalizing behavior problems and poor self-esteem to be present in twice as many children with a chronic disease as opposed to healthy children. Cardiac diseases related to significant problems in overall adjustment in patients. More adjustment problems and behavioral symptoms were also reported in children with chronic arthritis (37), children with asthma (38), and children with mild forms of sickle cell disease (39). Depressive symptoms were found in children with physical disorders (40) but not in children with rheumatic disease (41). Research on the self-concept in children with chronic disease reveals ambiguous results (42). A non-categorical approach to childhood illness was suggested in order to understand commonalities and differences that occur across disorders (2). Commonalities across diseases include visibility of the condition, whether the illness is life threatening, affects the sensory/motor systems, involves demanding or intrusive care, or involves learning difficulties. We found in our study sample more social and attention problems, lower competence in school activities and more aggressive behavior in children with CHD. The children themselves indicated to



experience more depressive symptoms than healthy children did. To conclude, our study results are in accordance with studies on children with chronic disease. It has been hypothesized that for less observable behavior as emotional functioning, parent-child agreement is weaker (12), which was confirmed in our study. Parents of the patient group did not rate higher anxiety/depression in their children while the children themselves indicated more feelings of depression. Possibly, parents misinterpret certain symptoms as aggressive or socially incompetent behavior while these actions might be the child’s expression of a depressed mood. As shown in previous studies (9), these children display obvious language deficits, so, it is not surprising that they might act out depressive emotions instead of verbalizing them. Our study is overall in agreement with previous studies on children with CHD, but it assembles both parental, self-reports of a patient group, and matched control group, by means of valid and reliable measures over a period of 6 to 12 years follow up. Equally, our study results are in accordance with studies on children with chronic disease in which general adjustment problems, internalizing and externalizing behavior problems appear significantly more than in healthy children. However, we could not identify the poor self-esteem that was found in children with chronic disease. A non-categorical approach to childhood illness (2) in order to understand commonalities and differences that occur across disorders might be suitable in further studies. Commonalities across diseases include visibility of the condition, whether the illness is life threatening, affects the sensory/motor systems, involves demanding or intrusive care, or involves learning difficulties (2). Studying the impact of these commonalities across disorders on behavioral and emotional functioning instead of studying different diagnostic groups is a possible option in future research. This study should be viewed in light of some limitations. It might be argued that generalization of our findings is limited because the study group consisted only of CHD-children that were full-time school attendees while children with non-cardiac malformations or genetic abnormalities were excluded. The inclusion of CHD-children with obvious neurological symptoms, which are unable to attend school full-time, would probably give rise to more negative ratings of self-perception and quality of life. However, we specifically chose to include a group of CHD-children that were considered to function normally in daily life in order to detect possibly covert behavior problems or poor self-perception. Because of our small patient sample that mainly consisted of children with mild to no residual defects (New York Class I and II), we were unable to draw conclusions on the effect of the severity of CHD on behavior and self-perception. There are indications that children with a cyanotic form of congenital heart defect are at higher risk for developing anxiety, depression, and behavioral problems (34), but future studies should elaborate this finding.



Future work should also try to elucidate the effect of different perfusion techniques on mid- term behavioral and psychosocial outcome in children with CHD. However, it will be indispensable to include parenting style and to control for the presence of the vulnerable child syndrome. Incorporating the amount and kind of psychosocial support the parents had during the upbringing of their child should make it possible to differentiate between the effect of new perfusion techniques and psychosocial support on behavioral and emotional outcome in children with CHD. Further, the adjustment of a child to a chronic illness depends on both the child’s characteristics and on the family’s reactions to stress. In this study, we mainly focused on the child’s characteristics. Future research needs to include the family’s perception of the heart defect and the family climate because they seem to influence the self-esteem of the child (5). In order to improve quality of life in children, adolescents and adults with a CHD, it has become crucial for the cardiology team to specifically ask the patient and the caregivers about his or her behavior, emotional functioning, and social situation. Until now, many emotional and behavioral symptoms in children, which might cause lower quality of life in these patients when they reach adulthood, are overlooked, and thus untreated. Neurodevelopmental, emotional and behavioral assessments at regular basis will result in early identification of those children in need of interventional programs. In the event that there is not a multidisciplinary cardiology team available for follow-up, the cardiologist should address psychosocial functioning. If issues are identified then appropriate referrals, tailored to the needs of the child and the family, should be made as soon as possible. Referral to a psychologist in case of emotional disturbance or coping problems and/or to a neuropsychologist in the specific case of school problems and learning disabilities, is advisable.



C o n c l us i o n

In this study, parents of CHD-children described their children to be less competent in school, having worse school performances and having a higher need for repeating a school year. Additionally, they saw social and attention problems as well as more aggressive behavior in their children. The children themselves did not rate their competence in school, social acceptance, sportive skills, physical appearance, behavior or global self-worth to be different to that of healthy peers. They were not more anxious than peers were, but they did indicate more depressive symptoms. We emphasize the importance of early recognition of behavior problems in children with CHD because of the importance of timely referral for interventional programs.



R e f e r e n c e s

1. Wray J, Sensky T. Psychological functioning in parents of children undergoing elective cardiac surgery. Cardiol Young 2004; 14: 131-139.

2. Lavigne JV, Faier-Routman J. Psychological adjustment to pediatric physical disorders: a meta-analytic review. J Pediatr Psychol 1992; 17: 133-157.

3. Nolan T, Pless B. Emotional correlates and consequences of birth defects. J Pediatr 1986; 109: 201-216.

4. Van Rijen E, Utens E, Roos-Hesselink J, et al. Psychosocial functioning in the adult with congenital heart disease: a 20-33 years follow-up. Eur Heart J 2003; 24: 673-683.

5. Aldén B, Gilljam T, Gillberg C. Long-term psychological outcome of children after surgery for transposition of the great arteries. Acta Paediatr 1998; 87: 405-410.

6. Casey F, Sykes D, Craig B, et al. Behavioral adjustment of children with surgically palliated complex congenital heart disease. J Pediatr Psychol 1996; 21 (3): 335-352.

7. Utens E, Verhulst FC, Meijboom FJ, et al. Behavioral and emotional problems in children and adolescents with congenital heart disease Psychol Med 1993; 23: 415-424.

8. Oates RK, Turnbull JA, Simpson JM, et al. Parent and teacher perceptions of child behavior following cardiac surgery. Acta Paediatr 1994; 83: 1303-1307.

9. Hövels-Gürich H, Konrad K, Skorzenski D, et al. Long-term neurodevelopmental outcome and exercise capacity after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy. Ann Thorac Surg 2006; 81: 958-967.

10. Utens E, Verhulst FC, Erdman RA, et al. Psychosocial functioning of young adults after surgical correction for congenital heart disease in childhood: a follow up study. J Psychosom Res 1994; 38: 745-758.

11. Hövels-Gürich, H, Konrad K, Wiesner M, et al. Long term behavioral outcome after neonatal arterial switch operation for transposition of the great arteries. Arch Dis Child 2002; 87: 506-510.

12. Krol Y, Grootenhuis M, Destrée-Vonk A, et al. Health related quality of life in children with congenital heart disease. Psychol Health 2003; 18 (2): 251-260.



13. Gupta S, Mitchell I, Giuffre R, et al. Covert fears and anxiety in asthma and congenital heart disease. Child Care Health Dev 2001; 27 (4): 335-348.

14. Wray J, Sensky T. How does intervention of cardiac surgery affect the self-perception of children with congenital heart disease? Child Care Health Dev 1998; 24 (1): 57-72.

15. Chen C, Li C, Wang J. Self-concept: comparison between school-aged children with congenital heart disease and normal school-aged children. J Clin Nurs 2005; 14: 394-402.

16. McKenzie DE, Andropoulos DB, DiBardino D, et al. Congenital Heart Surgery 2005: The brain: It’s the heart of the matter. Am J Surg 2005; 289- 294.

17. Bellinger DC, Wypij D, duPlessis AJ et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003; 126: 1385-1396.

18. Hövels-Gürich HH, Seghaye MC, Däbritz S, et al. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114: 578-585.

19. Limperopoulos C, Majnemer A, Shevell MI, et al. Predictors of developmental disabilities after open-heart surgery in young children with congenital heart defects. J Pediatr 2002; 141: 51-58.


21. Bruns LA, Chrisant MK, Lamour JM, et al. Carvedilol as therapy in pediatric heart failure: An initial multicenter experience. J Pediatr 2001; 138 (4): 505-511.

22. Achenbach TM. Manual for the Child Behavior Checklist/ 4-18 and 1991 profile. Burlington, VT: University of Vermont; 1991.

23. FC, van der Ende J, Koot HM. Praktische handleiding voor de CBCL. Van Gorcum, Asse; 1990.

24. Harter S. Manual for the self-perception profile for children. Denver, Colorado: University of Denver; 1985.

25. Veerman JW, Straathof MA, Treffers DA, et al. Competentiebelevingsschaal voor kinderen, Handleiding. Swets Test Publishers, Lisse, The Netherlands; 1997.



26. Van Rossum JH, Vermeer A. Competentiebelevingsschaal voor kinderen – Motorische Competentie- Zelfbeoordeling, Handleiding. Swets Test Publisher, Lisse, The Netherlands; 2000.

27. Kovacs M. Children’s Depression Inventory. New York: Multi-Health Systems; 1992.

28. Timbremont B, Braet C. Children’s Depression Inventory, Manual, Dutch translation. Swets Test Publisher, Lisse, the Netherlands; 2002.

29. Spielberger CD, Edwards CD, Lushene RE, et al. The State-Trait Anxiety Inventory for Children (preliminary manual). Palo Alto: Consulting Psychologists Press; 1973.

30. Bakker FC, van Wieringen PC, van der Ploeg HM, et al. Handleiding bij de Zelf-Beoordelings-Vragenlijst voor kinderen, ZBV-K. Swets and Zeitlinger, Lisse, the Netherlands; 1989.

31. Ternestedt BM, Wall K, Oddsson H, et al. Quality of life 20 and 30 years after surgery in patients operated on for Tetralogy of Fallot and for Atrial Septal Defect. Pediatr Cardiol 2001; 22: 128-132.

32. O’Dougherty M, Berntson G, Boysen S, et al. Psycho-physiological predictors of attentional dysfunction in children with congenital heart defects. Psychophysiology 1988; 25: 305-315.

33. Hockenberry-Eaton M, Dilorio C, Kemp V. The relationship of illness longevity and relapse with self-perception, cancer stressors, anxiety, and coping strategies in cancer. J Pediatr Oncol Nurs 1995; 12, 71-79.

34. Gupta S, Giuffre RM, Crawford S, et al. Covert fears, anxiety and depression in congenital heart disease. Cardiol Young 1998; 8: 491-499.

35. Connolly D, Rutkowski M, Auslender M, et al. Measuring health-related quality of life in children with heart disease. Appl Nurs Res 2002; 15(2): 74-80.

36. Pearson SR, Boyce TW. The vulnerable child syndrome. Pediatr Rev 2004; 25(10):345-349.

37. LeBovidge JS, Lavigne JV, Donenberg GR, Miller MR. Psychological adjustment of children and adolescents with chronic arthritis: a meta-analytic review. J Pediatr Psychol 2003; 28: 29-39.

38. McQuaid EL, Kopel SJ, Nassau JH. Behavioral adjustment in children with asthma: a meta-analysis. J Dev Beh Ped 2001; 22: 430-439.



39. Midence K, McManus C, Fuggle P, Davies S. Psychological adjustment and family functioning in a group of British children with sickle cell disease: preliminary empirical findings and a meta-analysis. Br J Clin Psychol 1996; 35: 439-450.

40. Bennett DS. Depression among children with chronic medical problems: a meta-analysis. J Dev Beh Ped 1994; 19:149-169.

41. Miller JJ. 3rd. Psychosocial factors related to rheumatic diseases in childhood. J Rheumatol Suppl 1993; 38: 1-11.

42. Barlow JH, Ellard DR. The psychosocial well-being of children with chronic disease, their parents and siblings: an overview of the research evidence base. Child Care Health Dev 2006; 32 (1): 19-31.

6 Do parental ratings on cognition reflect neuropsychological outcome in congenital heart disease? 111

6 D o p a r e n t a l r a t i n g s o n c o g n i t i o n r e f l e c t n e u r o p s y c h o l o g i c a l o u t c o m e i n c o n g e n i t a l h e a r t d i s e a s e ?


Submitted for publication A b s tr ac t

Objective: To describe the parental view of the cognitive skills of their child with a surgically corrected congenital heart disease (CHD) and compare it to objectified cognitive measures in children with CHD 6 to 12 years postoperatively. Setting and Patients: Parents completed a questionnaire on several cognitive functions of their child. Children with various CHD and healthy controls (n=86, aged 8 years 8 months ± 1 year 6 months) underwent an abbreviated IQ-testing and a neurodevelopmental assessment. Results: Parents of the children with CHD more frequently indicated lower sustained attention (p< .05), lower divided attention (p< .001), more problems with memory and learning skills (p <. 05), and deficient gross motor functioning (p< .01) compared to the parents of healthy controls. Intellectual and neuropsychological assessment revealed a lower estimated full-scale IQ (p<.01), worse sensorimotor functioning (p<. 001), and lower performances on language (p< .001), attention/executive functioning (p< .05), and memory (p<. 05) in the CHD-group. Conclusion: Parents of children with CHD more frequently report problems with attention, memory, and gross motor skills. Objective measures showed problems with sensorimotor functioning, language, attention/executive functioning, and memory. In contrast to the general skepticism of parents as valid sources of information, the subjective and objective measures agreed overall. This study endorses the usefulness of a parental questionnaire and asks for the investigation of neurocognitive functioning at follow-up.


112 6 Do parental ratings on cognition reflect neuropsychological outcome in congenital heart disease?


Functional outcome studies in children with congenital heart disease (CHD) have identified developmental and neurological abnormalities in as many as 25% (1). Neuropsychological assessment in school-aged children showed IQ scores of the larger part of children with CHD to fall within the expected range (2, 3), although lower than in the general population (4). Mostly reported neurocognitive deficits are found in language (5, 6) and in psychomotor functioning (4, 7, 8, 9, and 10). Despite the presence of these deficits, the parents’ perception of the cognitive skills of their child remains unknown. Only one study investigated parental ratings on cognitive functioning. Parents rated the quality of life on the domains of motor functioning, cognitive functions, and autonomy to be lower in their CHD-children than in healthy children (11). In contrast to the investigation of cognitive functions, parents are often the main source of information when behavior and emotional functioning are concerned. The Child Behavior Checklist (CBCL) is a frequently used measure to rate the behavior in children. However, with the exception of attention problems, which have been reported in CHD-children (12), and school competence, no specific cognitive functions are included in this questionnaire. The parents’ possibility to indicate broader neurocognitive shortcomings is therefore considerably limited. Nevertheless, the primary caregivers’ perception of the child’s cognitive skills becomes very important. Children with CHD often rate their functional outcome as equal to the performances of healthy children (13, 14), while outcome studies report lower performances for children with CHD on f.i. cognitive functioning (4-10). Further, subjective ratings of cognitive functioning are not always a good reflection of objective dysfunctions (15). Thus, the purpose of this study was to describe the parental view of the cognitive skills of their child with a surgically corrected congenital heart disease (CHD) and compare it to objectified cognitive measures in children with CHD 6 to 12 years postoperatively. M e t h o ds


Patients with various congenital heart diseases, operated at the Ghent University Hospital, between 1995 and 1999, with a birth weight > 2000g, without perinatal problems, non-cardiac malformations, medical, psychiatric or genetic abnormalities (i.e. Down syndrome, velocardiofacial syndrome, and Di George syndrome) were invited to participate in the study. Medical data were collected from the patients’ files. We noted weight and length at birth, Apgar scores immediately after birth and after 10 minutes. In total, 43 patients (21 girls, 22 boys) who underwent an open-heart procedure for various congenital heart defects were included. For each child in the patient group, a healthy control



was included, matched on sex, age, and educational level. The Hollingshead Four Factor Index rated the socioeconomic status. This index uses education, occupation, sex, and marital status to determine a composite social status. Multiplying the Occupation scale value by a weight of 5 and the Education scale by 3 and summing these products computed the score (16). The raw scores range from 8 to 66, with higher scores reflecting higher socioeconomic status. All children (i.e. patients and controls) attended school full time. The healthy children were contacted through their school boards. All parents gave written informed consent and the local Ethical Committee approved the study. Procedures were in accordance with the recommendations found in the Helsinki Declaration (17). Q u e s t i o n n a i r e o n c o g n i t i ve s k i l l s

Parents completed a questionnaire that was constructed (by the first and last author) to trace the kind and severity of cognitive difficulties a child with CHD might experience. The questionnaire includes 15 questions concerning attention skills (sustained and divided attention), memory functioning (recall and learning), problem solving strategies (planning and executing), and motor skills (fine and gross). The parent is asked to indicate the frequency of the cognitive problem (never, sometimes, mostly, and always). I n t e l l e c t u a l a n d n e u r o p s y c h o l o g i c a l a s s e s s m e n t

After parental agreement to participate, the children were invited for a neuropsychological assessment of 2 to 3 hours duration. They were tested with a short form of the Wechsler Intelligence Scale for Children -3rd edition, Dutch version (WISC-III NL) including Information, Vocabulary, Picture Completion, and Block Design (18). A deviation IQ was calculated using the procedure suggested by Sattler (19). The neuropsychological battery consisted of all core subtests of the NEPSY (a developmental NEuroPSYchological assessment), measuring Attention and Executive Functioning, Memory, Language, Visual-spatial Skills, and Sensorimotor Functioning (20). S t a t i s ti c s

Statistical analyses were performed using the SPSS for Windows statistical software package (version 12.0). Demographics (age at the moment of testing, sex, and educational level of both parents), and outcome measures (IQ, NEPSY, questionnaire) were compared between the CHD-group and control group. Nominal data were analyzed with Chi-square statistics. Normality was checked by Kolmogorov-Smirnov tests. If the data were not normally distributed (questions of



the cognitive questionnaire), the non-parametric Wilcoxon Signed Ranks test was used. For normally distributed data, a MANOVA was used with group (patient or control) as a between subject factor and the estimated full scale IQ and the NEPSY domains as dependent variables, and paternal level of education as a covariate. R e s ul t s


The CHD-group consisted of 43 children with various CHD. The group of children with a cyanotic CHD (n = 26) consisted of: transposition of the great arteries (TGA) (n = 5), tetralogy of Fallot (TOF) with or without ASD type II (n = 18), totally anomalous pulmonary venous connection (n = 1), truncus arteriosus (n = 2). The acyanotic group consisted of 17 children: atrial septal defect (ASD) (n = 9), ventricular septal defect (VSD) (n=6), pulmonic stenosis (n = 1) and aortic stenosis (n = 1). All children underwent an open-heart operation, aged <12 months, by means of full flow cardiopulmonary bypass under moderate hypothermia (25°C-33°C). Mean age at testing of the CHD- group was 8 years 8 months (SD 1 year 6 months). Because of careful matching, no significant group differences on sex and age at testing were found between the CHD-group and the healthy control group. There was a significantly lower length at birth (p<.05) in the CHD- group compared to the healthy control group. We did not find significant differences in Apgar scores. No group differences were found on maternal level of education or on socioeconomic status. The majority of children came from middle class families (skilled craftsmen, clerical and sales workers). We did find a lower paternal educational level in the CHD-group, so this variable was entered as a covariate in all statistical analyses. At the time of testing, all children (i.e. the CHD-group and healthy controls) attended school full time and according to their parents they participated actively in sports and social activities. Demographics and medical data can be found in Table 1. No differences were found between the cyanotic and the acyanotic group.



Table 1. Demographics and medical data of the CHD-group and the control group

Variable CHD- group n=43

Control group n=43

F¥ p

Age 8y8m ± 1y6m 8y11m± 1y7m .644 .829

Sex 22 ♂ 21♀ 22 ♂ 21 ♀ .047 † .571

Birth weight (g) 3094 ± 741 3385 ± 600 3.65 .060

Birth length (cm) 48.9 ± 3.1 50.4± 2.4 5.78 .019*


< 4: 15.8%

4 – 7: 0%

7 –10: 84.2%

< 4: 6.5%

4 – 7: 0%

7 – 10: 93.5%

-1.73‡ .059

Apgar after 10 min < 4: 4.7%

4 -7: 0%

7-10: 89.5 %

< 4: 0%

4 – 7: 3.2 %

7 – 10: 96.8%

-1.41‡ .157

Education father (years) 12.9 ± 2.0 14.3 ± 3.4 4.86 .031*


13.0 ± 1.9 13.7 ± 2.9 1.70 .197

Mean Hollingshead SES

32.4 ± 8.4 35.6± 11.2 2.80 .135

¥ : degrees of freedom [1, 81], †: χ² value, ‡: Wilcoxon Signed Ranks Test, SES: socioeconomic status, level of significance *p< .05, ** p< .001

Q u e s t i o n n a i r e o n c o g n i t i ve s k i l l s

Parental reports on the cognitive skills of CHD-children revealed a significantly higher percentage of CHD-children to display problems with sustained attention (p < .05), divided attention (p < .001), memory and learning skills (p <. 05), and gross motor functioning (p < .01) compared to healthy peers. In Table 2, the questionnaire and the frequency ratings of the parents of the CHD-group and the healthy group on each question can be found. No differences were found between the cyanotic and the acyanotic group.



Table 2. Response pattern on the cognitive questionnaire

CHD-group n=43

frequency

Control group n=43

frequency

p

Attention

1. My child has problems keeping attention focused for a long time (f.i. when watching television or playing games)

never: 28.6% sometimes: 47.6%

mostly: 16.7% always: 7.1%


mostly: 5.3% always: 0%

.021*

2. My child has problems sustaining mental work (f.i. when studying)





.021*

3. To perform well, my child has to work slower than peers





< .001***

4. My child has problems doing two tasks simultaneously

never: 9.8% sometimes: 39.0 %




< .001***

5. My child is highly distractible never: 7.1% sometimes: 50.0%




.074

6. My child reacts slower to questions or situations than peers




mostly: 0% always: 0%

< .001***

Memory

7. My child is forgetful (f.i. forgets to do homework, forgets necessary school material)





.188

8. My child can not remember certain events or assignments





.014*



CHD-group

n=43 frequency

Control group n=43

frequency

p

9. My child has problems learning new information (f.i. summaries)





.002**

Problem solving

10. My child has problems planning activities





.129

11. My child has problems with decision making





.414

12. When a task demands multiple steps, my child has problems determining the order of the steps





< .001***

Motor functioning

13. The handwriting of my child is less legibly than that of peers





.417

14. My child has problems with fine motor tasks (f.i. cutting straight, colouring, threading beads)





.207

15. My child has problems with gross motor tasks (f.i. swimming, running, gymnastics)

never: 52.4% sometimes: 33.3 %




.005**

Level of significance * p < .05, ** p< .01, * ** p< .001




On the short form intelligence battery, the children in the CHD-group performed significantly lower than healthy peers (p < .01). Also on the NEPSY domains Language (p < .001), Sensorimotor functioning (p < .001), Attention and executive functioning (p < .05) and Memory (p < .05), group differences emerged. Results on the intellectual and neuropsychological performances of the CHD-group and the control group are summarized in Table 3. No differences were found between the cyanotic and the acyanotic group.

Table 3. Performances on the Estimated Full Scale IQ and the NEPSY domains (M±SD)

Variable CHD- group n=43

Control group n=43

F¥ p

Estimated Full Scale IQ Attention/ executive functioning Memory Language Visual-spatial skills Sensorimotor functioning

95.6 ± 15.4 112.5 ± 10.1

98.4 ± 14.0 102.0 ± 11.8 115.0 ± 15.7 88.8 ± 13.4

107.0 ± 15.1 117.8 ± 9.2

105.7 ± 12.3 115.8 ± 14.0 120.2 ± 12.7 101.1 ± 9.6

.833 5.80

6.56 20.0 1.27

18.59

.005*

.018*

.012* < .001**

.263 < .001**

¥ : degrees of freedom [1, 81], level of significance *p< .05, ** p< .001



D i s c u s s i o n

In this study, we described the parents’ view on cognitive functioning in their child with CHD, and characterized the neuropsychological profile of the child. Although shortcomings on the neuropsychological battery frequently supervene during developmental testing (4-10), the parents rarely mention them spontaneously during follow-up visits. To explore the parents’ view, we used a self-constructed questionnaire that measures their perception of the attention, problem solving, memory, and sensorimotor functioning of the child. On this questionnaire, parents of children with CHD report more problems with attention skills. A higher percentage of parents in the CHD-group indicated problems with keeping attention focused and sustained. They more frequently indicated slower working speed, difficulties with multitasking and slower reactions to questions than parents of healthy children did. On the questions regarding memory, problems remembering events and learning new information are reported, while forgetfulness is not. Planning and decision making appear normal according to the parents of children with CHD, but the child displays difficulties executing tasks when they become more complex. Difficulties with gross motor functions were also more frequently reported in the CHD-group while problems with handwriting and fine motor tasks were not reported. Intellectual and neuropsychological assessment revealed lower performances in the CHD-group compared to healthy children on the estimated full scale IQ, in accordance with previous studies (2, 3, and 4). Additionally, patients performed significantly worse on sensorimotor functions. Specifically problems imitating hand positions, slowing down in more complex motor tasks and worse hand-eye coordination was observed which has been repeatedly identified before and is in accordance with the consensus that both gross and fine motor skills are affected in children with CHD (6, 7, and 9). A second cognitive function that elicited significant differences between the groups was language. Lower phonological awareness, a deficient strategy to gain access to names of color, size, and shape, and a lacking ability to process and respond quickly to verbal instructions constituted the main shortcomings. These results corroborate with studies reporting dysfunction of speech in 40% of children with TGA (6), dysfunction in expressive language in 34.4% of TGA or VDS patients, and defective receptive language in 28.1% of this group (21). With regard to the cognitive functions attention/executive functioning and memory, previous research yielded conflicting results. Our study indicates an involvement of both functions in the neuropsychological profile of children with CHD, but to a lesser degree. It was mainly an impulsive test attitude that caused the lower results in the CHD-group on attention/executive functioning, while focused attention revealed no problems. The difference in memory performance between the CHD-group and the healthy control group was due to difficulties with both learning and recalling the names associated with the faces presented.



It is surprising that both the objective and the subjective measures indicate the presence of neuropsychological shortcomings in these children with CHD, who are considered to function normally and who attend school full time. In contrast to the general skepticism of parents as valid sources of information, the subjective and objective measures agreed overall. Both parents and neuropsychological assessment clearly indicate the presence of a broad range of neurocognitive difficulties, hereby reflecting the necessity to explicitly question cognitive skills of children with CHD. So, despite of the seemingly normal general status of the child, combining neuropsychological assessment and the use of parental reports at regular basis becomes advisable. Neuropsychological assessment should be performed because early detection will prevent subtle neurocognitive deficits to worsen over time and limit the academic achievement and quality of life in children with CHD. Parental questionnaires and self-reports on functional outcome will elucidate the perception of all parties involved, and might create a possibility to remediate false beliefs on functional outcome and work on parenting styles such as being too protective, (overly) concerned or pampering the child. A holistic approach should therefore be applied in the follow-up care for children, adolescents, and adults with CHD. Future studies should strive for larger patient samples, refine the questions, and statistically enhance the questionnaire. Nevertheless, this study gave the initial impetus to the usefulness of parental questionnaires when neurocognitive functioning in children with CHD is concerned.



R e f e r e n c e s

1. Bellinger DC, Wypij D, Kuban KCK, Rappaport LA, Hickey PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999; 100: 526-532.

2. Dickinson DF, Sambrooks JE. Intellectual performance in children after circulatory arrest with profound hypothermia in infancy. Arch Dis Child 1979; 54: 1-6.

3. Haneda K, Itoh T, Togo T, Ohmi M, Mohri H. Effects of cardiac surgery on intellectual function in infants and children. Cardiovasc Surg 1996; 4: 303-307.




7. Wright M, Nolan T. Impact of cyanotic heart disease on school performance. Arch Dis Child 1994; 71: 64-70.

8. Oates RK, Simpson JM, Cartmill TB, Turnbull JAB. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child 1995; 72: 298-301.

9. Hövels-Gürich HH, Seghaye MC, Däbritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114: 578-585.

10. Limperopoulos C, Majnemer A, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov C, et al. Predictors of developmental disabilities after open-heart surgery in young children with congenital heart defects. J Pediatr 2002; 141: 51-58.

11. Krol Y, Grootenhuis M, Destrée-Vonk A, Lubbers L, Koopman H, Last B. Health related quality of life in children with congenital heart disease. Psychol Health 2003; vol 18, n° 2: 251-260.



12. O’Dougherty M, Berntson G, Boysen S, Wright F, Teske D. Psycho-physiological predictors of attentional dysfunction in children with congenital heart defects. Psychophysiology 1988; 25: 305-315.

13. Casey F, Sykes D, Craig B, Power R, Mulholland H. Behavioural adjustment of children with surgically palliated complex congenital heart disease. J Pediatr Psychol 1996; 21 (3): 335-352.

14. Utens E, Verhulst FC, Erdman RA, Meijboom FJ, Duivenvoorden HJ, Bos E, et al. Psychosocial functioning of young adults after surgical correction for congenital heart disease in childhood: a follow up study. J Psychosom Res 1994; 38: 745-758.

15. Dodrill C. Myths of neuropsychology. Clin Neuropsychol 1997; 11 (1): 1-17.

16. Hollingshead AB. Four Factor Index of Social Status. New Haven, CT: Yale University, Department of Sociology, 1975.





21. Hövels-Gürich H, Seghaye M, Sigler M, Kotlarek F, Bartl A, Neuser J, et al. Neurodevelopmental outcome related to cerebral risk factors in children after neonatal switch operation. Ann Thorac Surg 2001; 71: 881-888.

7 General Discussion 123

7 G e n e r a l D i s c u s s i o n


124 7 General Discussion


Follow-up studies have identified developmental and neurological abnormalities in as many as 25% of survivors (Bellinger et al, 1999). Despite the high incidence of CHD, psychological and neuropsychological research in this population remains scarce. The difficult medical circumstances and methodological constraints for research in this population play an important part in this scarcity. The functional testing that can be completed on neonates is extremely limited and the illness of the child reduces the predictive validity of a preoperative functional assessment. Many studies covering neurodevelopment were conducted on infants and children 1 to 4 years after surgery. However, at that age it is unclear whether the neurodevelopmental delay is due to a maturational lag or to a more permanent impairment. The aim of the study was to specify the functional outcome in children with a surgically corrected CHD, 6 to 12 years postoperatively as measured by intellectual, neuropsychological, behavioral, and emotional variables. Both parents and children were used as informants. We will now discuss each goal we set up in this study, as mentioned in the section goals and methodology in chapter 1. D e s c r i b i n g t h e n e u r o p s y c h o l o g i ca l p r o f i l e i n c h i l d r e n w i t h s u r g i c a l l y c o r r e c t e d C H D 6 t o 1 2 y e a r s p o s t o p e r a t i v e l y .

The current study results (chapter 2) indicate a significant relation between surgically corrected CHD and specific neurocognitive difficulties during school age. In accordance with previously published studies (Dickinson & Sambrooks, 1979; Haneda et al, 1996; Wray & Senksy, 1999), we found the estimated intellectual capacities of children with surgically corrected CHD to fall within the expected range, although significantly lower than in our healthy group. On the neuropsychological assessment, the most striking deficits are on sensorimotor functioning and language. We found up to 25% of the children with CHD to perform worse than expected on motor tasks. Children with CHD had significantly reduced skills to imitate hand and finger positions, were slower on motor tasks, and showed worse hand-eye coordination than the healthy control group. Moreover, they displayed an impulsive test strategy. The slowing down in more complex motor tasks and worse hand-eye coordination has been repeatedly identified and is in accordance with the consensus that both gross and fine motor skills are affected in children with CHD (Wright & Nolan, 1994; Hövels-Gürich et al, 1997; Hövels-Gürich et al, 2002a). Inefficient processing of tactile and kinesthetic information seems the most plausible explanation for the poor sensorimotor performance in the CHD-group (Korkman et al, 1998). In an attempt to identify the cause of these sensorimotor deficits, we suspected the involvement of the basal ganglia in the motor deficits found in our study. Previous studies demonstrated decreases in the



basal ganglia N-acetylaspartate levels to be correlates for neuropsychological sequelae as for instance motor speed (Ariza et al, 2004). However, we do have to keep in mind that we did not dispose of brain imaging results, which leaves the presence of periventricular leukomalacia or other brain damage in our study group unknown. This major form of brain injury results in behavioral alterations, motor disturbances, and learning disabilities (Fan et al, 2005), and occurs in over 50% of neonates that underwent cardiac surgery (Galli et al, 2004). Future structural and functional MRI studies can be useful in clarifying the relationship between motor deficits and brain (dys) functions of the child with CHD. A second neuropsychological function in which children with CHD performed significantly lower is language. These children had lower phonological awareness, showed a deficient strategy to gain access to names of color, size, and shape, and lacked the ability to process and respond quickly to verbal instructions of increasing difficulty. These results corroborate with studies in children with TGA or VSD, in which dysfunction of speech was found in 40%, expressive language was found to be reduced in 34.4%, and receptive language seemed defective in 28.1% (Hövels-Gürich et al, 2001; Hövels-Gürich et al, 2002a). Poorer performances in reading and spelling are recognized as well (Wray & Sensky, 2001) and can be explained by a deficient retrieval of sound-symbol associations and spoken-written word connections involved in reading acquisition (Korkman et al, 1998). Although memory tasks are usually performed within the normal range (Hövels-Gürich et al, 2001; Visconti et al, 1999), the children with CHD showed significantly lower results on memory tasks. Making a cross-modal association (between verbal and visual information) is particularly difficult for children with CHD, who display difficulties with both learning and recalling the names associated with the faces presented. A possible involvement of the hippocampus, vulnerable to hypoxia (Towfighi et al, 1997), should be investigated further. Our results indicate no problems concerning focused auditory attention, but behavioral observation during the testing revealed poor impulse control on an executive task and during a visual attention task. Impulsivity in behavior has been previously reported in children with acyanotic CHD (Visconti et al, 1999). Another explanation to bear in mind is a deficiency in frontal lobe functioning, which has been postulated before in adult patients with CHD (Daliento et al, 2005). In contrast to previous studies (Bellinger et al, 2003), visual-spatial skills did not elicit differences between the CHD-group and the healthy controls. The children had no problems copying designs and estimating line orientation and directionality. To identify differences within the CHD-group, we divided the CHD-group in a cyanotic and acyanotic CHD- group. Although it is expected that, due to the difference in severity of the symptoms, cyanotic forms of CHD result in lower functional outcome than acyanotic forms of CHD (Wray & Sensky, 2001), this is not always supported by clinical evidence (Haneda et al, 1996; Oates et al, 1995). In



this study, the cyanotic and acyanotic CHD-groups did not display any differences on the intellectual and neuropsychological evaluation. Low-flow cardiopulmonary bypass is called superior to CA because it supposedly does not impair cerebral perfusion (Scallan, 2003). However, this finding was countered by the Boston Circulatory Arrest study that could not show a significant difference between these support methods on neurological testing 8 years after surgery (Ungerleider et al, 2004). Equally, all children in our study were operated on by means of low-flow perfusion techniques under moderate hypothermia; yet neuropsychological testing still displays shortcomings. Attention should further be drawn to the fact that the children in our study were identified as hemodynamically stable and that these children often remain merely under cardiac control, while neurocognitive deficits are left unattended. However, trying to identify a cause for the adverse neuropsychological outcome, preoperative, operative, as well as postoperative variables should be brought under attention. Possibly, a combination of several factors constitutes a child profile prone to adverse outcome. This study contains some limitations. By means of the Child Behavior Checklist, we found out that in the patient group 25.6% and in the control group 2.5% of the children received speech therapy. Because we did not further question the kind and amount of interventional programs the child underwent in a standardized manner (physiotherapy, speech therapy, …), we are unable to report on the possible impact of therapy on the dysfunctions mentioned. The neuropsychological performances of the children receiving speech therapy did not differ significantly from the children who did not. We can conclude that although the remedial therapy in 25.6% of the patient group might have ameliorated the performances in these children, they still display significantly lower neuropsychological performances compared to healthy children. Second, parents of children with a congenital heart disease entered the study voluntarily. The suspicion of a neurodevelopmental or behavioral problem in their child might have been the parent’s motivation for participation, while parents of children that perform well at school, may have wished not to stigmatize their child as a patient. The neurodevelopmental status of the child with a congenital heart disease can be visualized on a continuum. At the negative end, children with severe neurological dysfunction are found; at the positive end, children with a normal neurodevelopment are located. The children in our study can probably be situated in the middle of this continuum. We deliberately excluded children with severe neurological dysfunction; the nature of the selection procedure most likely filtered out the children with normal neurodevelopment. Overall, our study is in accordance with previous research but its strength lies in the identification of specific neurocognitive shortcomings, by means of comprehensive neuropsychological assessment in children with various CHD in an older age range



than previous studies. Previously studied broad cognitive functions can now be narrowed down to specific deficits and we can now rate the degree of these relative deficits. While previous studies identified neurological deficits in young children, our study highlights the persistence of certain deficits up to school age. The possible involvement of specific brain regions susceptible to hypoxia such as basal ganglia, frontal lobes, and hippocampus in the neuropsychological profile has to be elucidated in future studies. C o m p a r i n g f u n c t i o n a l o u t c o m e i n c y a n o t i c C H D , a cy a n o t i c C H D a n d h e a l t h y c h i l d r e n .

In this outcome study (chapter 3), we compared the intellectual, neuropsychological, and behavioral function of children with TOF, 6 to 12 years postoperatively to a group with acyanotic CHD, and to healthy peers. We could not identify any functional outcome differences between the TOF-group and the acyanotic group. In the TOF-group, we identified a lower estimated full-scale intelligence and a neuropsychological profile characterized by mainly mild motor deficits and difficulties with language tasks. Attention problems and lower school competencies are the most important behavioral aspects parents of children with TOF reported. In general, our findings are comparable to most outcome studies on children with CHD as discussed in chapter 2. However, these results contradict the general belief that due to the difference in severity of the symptoms, cyanotic forms of CHD result in lower functional outcome than acyanotic forms of CHD (Wray & Sensky, 2001). This hypothesis was countered by studies that did not identify any differences on neuropsychological outcome between a cyanotic and acyanotic CHD-group (Haneda et al 1996; Oates et al, 1995). Possibly, the small sample size prevented the differences to emerge. The relative difference in hypoxemia between both groups might have been too small to produce differences in neuropsychological outcome. On the other hand, preoperative and postoperative factors might play a more crucial role in the outcome of children with CHD compared to the surgical intervention. I d e n t i f y i n g m e d i ca l a n d s u r g i ca l p r e d i c t o r s o f n e u r o p s y c h o l o g i c a l d e f i c i t s i n s ch o o l - a g e d c h i l d r e n w i t h a s u r g i ca l l y co r r e c t e d c o n g e n i t a l h e a r t d i s e a s e .

Although literature on outcome measures in children with congenital heart defects primarily focused on cerebral injury related to cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), the etiology of neurological and neuropsychological deficits is known to be multifactorial with preoperative, peri-operative, and postoperative factors contributing to the outcome. Various factors have been revised separately but the cumulative impact of several pre-, peri-, and postoperative factors on the neuropsychological functioning of children with



surgically corrected CHD still yields conflicting results. We could not identify any medical or surgical predictors for the adverse neuropsychological outcome in children with CHD 6 to 12 years postoperatively, as described in chapter 2. A multitude of risk factors might have contributed to the neuropsychological outcome of children with CHD and undoubtedly, certain risk factors were not included such as structural brain imaging, neurological examination, or polymorphisms of apolipoprotein E. Despite the usefulness of the search for predictors of adverse outcome, it should be kept in mind that the larger part of children with CHD displays a normal neurocognitive development. Contemporary surgical techniques result in better stabilization of the cardiac status and operations are performed at early age. Plasticity of the brain can play an important role in the reorganization of the brain or compensation by other brain regions after possibly occurred damage. This brain plasticity might be, at least partially, responsible for the normal neurodevelopmental status of the larger part of children with CHD. Future studies should strive for the identification of demographic, medical, pre-, peri- and postoperative predictors of adverse neuropsychological outcome in children with CHD in order to provide accurate and reliable information to the parents concerning the postoperative functional outcome of their child. D e s c r i b i n g t h e b e h a vi o r , t h e e m o t i o n a l f u n ct i o n i n g , a n d s e l f - p e r ce p t i o n o f ch i l d r e n w i t h s u r g i ca l l y c o r r e c t e d C H D 6 t o 1 2 y e a r s p o s t o p e r a t i v e l y .

In chapter 5, we questioned, in a standardized manner, both parents and children with a surgically corrected congenital heart defect on the competence and behavior of the child, 6 to 12 years postoperatively. Parental reports revealed no differences between the patient group and the control group concerning participation in activities and social skills. However, the parents found their children to be significantly less competent in school skills than healthy control children. They also reported lower school results and more school problems in general. Additionally, a higher percentage of CHD-children had repeated a school year. These results are in accordance with previous follow-up studies in adolescents and adults that report patients to have spent longer periods in school (O’Dougherty et al, 1988), display more need for special education and more often present with a learning disorder (Van Rijen et al, 2003). On the problem behavior scales, parents of CHD-children judged them to have more social problems, more attention problems and to display more aggressive behavior than children from the healthy control group. Social problems (Casey et al, 1996), oppositional defiant behavior (Aldèn et al, 1998), as well as a higher risk for attention problems (Bellinger et al, 2003) have been reported previously. The attention problems are confirmed in broader neuropsychological outcome studies. Motor and language difficulties, some memory



and attention problems and deficits in executive functioning also appeared in this group (Hövels-Gürich et al, 2001; Scallan, 2003; Hövels-Gürich et al, 2006; Wray & Senksy, 1998). These neuropsychological failings were probably and at least partially responsible for the shortcomings at school level. Although the children in our study group were operated by means of new perfusion techniques, avoiding the use of circulatory arrest and therefore adverse neurodevelopmental outcome, parents still report lower school results and school problems in general. The benefits of these new perfusion techniques on neuropsychological and developmental outcome remain to be examined. Equally, pre-and postoperative factors should be brought under attention in order to identify a child profile, prone to adverse functional outcome. The children’s self reports on perceived competence at school, social acceptance, athletic skills, physical appearance, behavior, and self-esteem, did not elicit significant differences compared to the ratings of the healthy children. These results corroborate with other studies that did not find group differences on self-perception and quality of life (Utens et al, 1994; Hövels-Gürich, 2002b). Although many studies have proved motor deficits to be common in this group (Hövels-Gürich et al, 1997; Limperopoulos et al, 2002), the children themselves rated their motor competences equal to those of healthy peers, and estimated motor functioning equally important in daily life. We could thus not confirm the previously reported self-perception of reduced motor functioning and reduced autonomy (Krol et al, 2003). A possible explanation for these positive ratings can be social desirability or denial mechanisms, used as coping mechanisms. Repressing or even denial early in life might help normalize functioning, although, it might also obscure emotional distress (Horner et al, 2000). A more plausible explanation might be the transitional state these children find themselves in. The worst period of surgical procedures and frequent hospitalizations has passed and future issues such as recurring cardiac symptoms or threatened life expectancy are not yet a concern. Although anxiety and depression are more frequent in a pediatric cardiac population (Casey et al, 1996; Wray & Sensky, 1998; Gupta et al, 1998), our results only support the presence of depressive symptoms. Frequent hospital visits and not being able to fully participate in sport and social activities restrains the social involvement and acceptance by peers, which might be a reason for a dysthymic state. Overall, while parents of CHD-children reported more behavioral and especially school problems, the children themselves did not indicate lower perceived competence on school skills or any other skill included. Conflicting results between parental and child reports might reflect the tendency of parents to be overprotective and overly concerned about the physical and psychological status of their child. Parental reactions to an acute, life-threatening illness in a child that may have long-term psychologically deleterious effects on both parents and children has been recognized as a clinical entity called the vulnerable child syndrome (Pearson & Boyce, 2004).



Further, previous studies have reported later adjustment of the child with CHD to depend on several factors including emotional state of the parents (Utens et al, 1993) and parental attitude such as pampering and being overprotective (Utens et al, 1994). Since we did not include parenting style, or measures that might indicate the presence of the vulnerable child syndrome (such as The Vulnerable Child Scale), we can only speculate on the presence of this syndrome and on the possibility that parental perceptions might have influenced the reported results. Our study is overall in agreement with previous studies on children with CHD, but it assembles parental and child reports, includes a matched control group and uses valid and reliable measures over a period of 6 to 12 years follow-up. C r e a t i n g t h e p o s s i b i l i t y f o r p a r e n t s t o r e p o r t o n co g n i t i v e d e f i c i t s b y m e a n s o f a q u e s t i o n n a i r e .

In chapter 6, we described the parents’ view on cognitive functioning in their child with CHD, and characterized the neuropsychological profile of the child. While parents are often the main source of information when behavior is concerned, their possibility to indicate broader neurocognitive shortcomings is considerably limited. Although shortcomings on the neuropsychological battery frequently supervene during developmental testing (see chapter 2), the parents rarely mention cognitive problems spontaneously during follow-up visits. To explore the parents’ view, we used a self-constructed questionnaire that measures their perception of the attention, problem solving, memory, and sensorimotor functioning of the child. On this questionnaire, parents of children with CHD reported more problems with attention skills. A higher percentage of parents in the CHD-group indicated problems with keeping attention focused and sustained. They more frequently indicated slower working speed, difficulties with multitasking and slower reactions to questions than parents of healthy children did. On the questions regarding memory, problems remembering events and learning new information are reported, while forgetfulness is not. Executive functioning such as planning and decision making appear normal. Yet, according to the parents of children with CHD, the child displays difficulties executing more complex tasks. Difficulties with gross motor functions were also more frequently reported in the CHD-group while less eligible handwriting and poor fine motor tasks were not mentioned. It is surprising that both the objective and the subjective measures indicate the presence of neuropsychological shortcomings in children with CHD, who are considered to function normally and who attend school full-time. In contrast to the general skepticism of parents as valid sources of information, the subjective and objective measures were overall in agreement. Both parents and neuropsychological assessment clearly indicate the presence of a broad range of neurocognitive



difficulties, hereby reflecting the necessity to explicitly question cognitive skills of children with CHD. So, despite of the seemingly normal general status of the child, combining neuropsychological assessment and the use of parental reports at regular basis becomes advisable. Neuropsychological assessment should be performed because early detection will prevent subtle neurocognitive deficits to worsen over time and limit the academic achievement and quality of life in children with CHD. Parental questionnaires and self-reports on functional outcome will elucidate the perception of all parties involved, and might create a possibility to remediate false beliefs on functional outcome and to work on parenting styles such as being to protective, (overly) concerned or pampering the child. A holistic approach should therefore be applied in the follow-up care for children, adolescents, and adults with CHD. R e c o m m e n da t i on s f or fu t u r e s t u di e s

Future studies should primarily be longitudinal. Follow–up of neonates on several domains (neuropsychology, behavior, emotions, and self-perception) could result in identifying predictors for adverse neurodevelopmental outcome at mid- or long-term.

Preoperative structural brain imaging and a neurodevelopmental testing

could be useful to interpret later adverse functional outcome.

Functional magnetic resonance imaging can elucidate the involvement of specific brain areas such as basal ganglia, hippocampus, and frontal lobe functioning in the neuropsychological deficits we observed.

Incorporating pre-, peri-, and postoperative variables might resolve in the

identification of predictors for adverse neuropsychological outcome. Possibly, a combination of several factors constitutes a child profile prone to adverse outcome.

Nowadays, psychosocial support for the parents is provided when the child

is diagnosed with a CHD. The kind and amount of guidance the parents had during the upbringing of their child might be an influencing factor on functional outcome, which cannot be ignored.

In case of the cognitive questionnaire, future studies should strive for larger

patient samples, refine the questions, and statistically enhance the questionnaire.



8 Conclusion 133

8 C o n c l u s i o n


134 8 Conclusion

C o n c l us i o n

At school age, children with CHD display neuropsychological deficits on formal testing. Equally, parents report more school problems, cognitive deficits, and social and aggressive problem behavior. The children themselves report more depressive symptoms, but rate their self-perception as equal to that of healthy peers. The use of parental information is recommended since their observations concur with objectified measures. The cause of these functional deficits should be further elucidated incorporating preoperative, peri-operative, and postoperative variables. Possibly, a combination of several factors constitutes a child profile prone to adverse outcome. Despite the seemingly normal general status of the child, neuropsychological, behavioral, and emotional assessment at regular basis becomes advisable. Neuropsychological assessment will lead to early detection of children at risk and will prevent subtle neurocognitive deficits to worsen over time. Hopefully, it will lead to improved academic achievement and quality of life in children with CHD. Parental questionnaires and self-reports on functional outcome will elucidate the perception of all parties involved, and might create a possibility to remediate false beliefs on functional outcome and to work on parenting styles such as being to protective, (overly) concerned or pampering the child. In order to improve quality of life in children, adolescents and adults with a CHD, the multidisciplinary team is recommended to specifically ask the patient and the caregivers about the functional outcome on several domains. Since the cardiologist mostly induces follow-up moments, and many hospitals do not have multidisciplinary teams at their disposal, he or she should address psychosocial functioning. Nevertheless, in order to provide correct referral as soon as possible, tailored to the needs of the child and its family, multidisciplinary follow-up will become inevitable. This study can also help psychologists, teachers, and caregivers to recognize children with CHD that need intervention. So, despite of the seemingly normal general status of the child, combining neuropsychological assessment and the use of parental reports at regular basis is necessary. A holistic approach should be applied in the follow-up care for children, adolescents, and adults with CHD.

References 135

R e f e r e n c e s

Achenbach TM. Manual for the Child Behavior Checklist/ 4-18 and 1991 profile. Burlington, VT: University of Vermont; 1991.

Aldén B, Gilljam T, Gillberg C. Long-term psychological outcome of children after surgery for transposition of the great arteries. Acta Paediatr 1998; 87: 405-410.

Ariza M, Junqué C, Mataro M, Poca M, Bargallo N, Olondo M, et al. Neuropsychological correlates of basal ganglia and medial temporal lobe NAA/Cho reductions in traumatic brain injury. Arch Neurol 2004; 61: 541-544.

Bakker FC, van Wieringen PC, van der Ploeg HM, Spielberger CD. Handleiding bij de Zelf-Beoordelings-Vragenlijst voor kinderen, ZBV-K. Swets and Zeitlinger, Lisse, the Netherlands; 1989.

Bellinger DC, Wypij D, Kuban KCK, Rappaport LA, Hickey PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999; 100 (5): 526-532.

Bellinger DC, Wypij D, duPlessis AJ, Rappaport LA, Jonas RA, Wernovsky G, et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003; 126: 1385-96.

Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E, Blume ED, et al. Carvedilol as therapy in pediatric heart failure: An initial multicenter experience. J Pediatr 2001; 138 (4): 505-511.

Casey F, Sykes D, Craig B, Power P, Mulholland HC. Behavioral adjustment of children with surgically palliated complex congenital heart disease. J Pediatr Psychol 1996; 21 (3): 335-352.


136 References

Daliento L, Mapelli D, Russo G, Scarso P, Limongi F, Iannizzi P, et al. Health related quality of life in adults with repaired tetralogy of Fallot: psychosocial and cognitive outcomes. Heart 2005; 91 (2): 213-218.

Dickinson DF, Sambrooks JE. Intellectual performance in children after circulatory arrest with profound hypothermia in infancy. Arch Dis Child 1979; 54: 1-6.

Fan LW, Lin S, Pang Y, Lei M, Zhang F, Rhodes P, et al. Hypoxia-ischemia induced neurological dysfunction and brain injury in the neonatal rat. Behav Brain Res 2005; 165: 80-90.

Galli K, Zimmerman R, Jarvik G, Wernovsky G, Kuypers M, Clancy R, et al . Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2004; 127: 692-704.

Grégoire, J. Comparison of three short forms of the Wechsler Intelligence Scale for children – Third Edition (WISC-III). Eur Rev Appl Psychol 2000; 50, 437-441.

Gupta S, Giuffre RM, Crawford S, Waters J. Covert fears, anxiety and depression in congenital heart disease. Cardiol Young 1998; 8: 491-499.

Haneda K, Itoh T, Togo T, Ohmi M, Mohri H. Effects of cardiac surgery on intellectual function in infants and children. Cardiovasc Surg 1996; 4: 303-307.

Harter S. Manual for the self-perception profile for children. Denver, Colorado: University of Denver; 1985.

Hoffman JI. Incidence of congenital heart disease: I. Postnatal incidence. Pediatr Cardiol 1995; 16: 103-113.

Horner T, Liberthson R, Jellinek M. Psychosocial profile of adults with complex congenital heart disease. Mayo Clin Proc 2000; 75: 31-36.

Hövels-Gürich HH, Seghaye MC, Däbritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114: 578-585.

Hövels-Gürich H, Seghaye M, Sigler M, Kotlarek F, Bartl A, Neuser J, et al. Neurodevelopmental outcome related to cerebral risk factors in children after neonatal switch operation. Ann Thorac Surg 2001; 71: 881-888.

Hövels-Gürich, H, Konrad K, Wiesner M, Minkenberg R, Herpetz-Dahlmann B, Messmer BJ, et al. Long-term behavioral outcome after neonatal arterial switch operation for transposition of the great arteries. Arch Dis Child 2002a; 87: 506-510.


References 137

Hövels-Gürich HH, Seghaye MC, Schnitker R, Wiesner M, Huber W, Minkenberg R, et al. Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 2002b; 124: 448-458.

Hövels-Gürich H, Konrad K, Skorzenski D, Nacken C, Minkenberg R, Phys D, et al. Long-term neurodevelopmental outcome and exercise capacity after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy. Ann Thorac Surg 2006; 81: 958-967.

Korkman M, Kirk U, Kemp S. NEPSY. A developmental neuropsychological assessment. The Psychological Corporation. A Harcourt Assessment Company; 1998.

Kovacs M. Children’s Depression Inventory. New York: Multi-Health Systems; 1992.

Krol Y, Grootenhuis M, Destrée-Vonk A. Health related quality of life in children with congenital heart disease. Psychol Health 2003; 18 (2): 251-260.

Limperopoulos C, Majnemer A, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov C, et al. Predictors of developmental disabilities after open-heart surgery in young children with congenital heart defects. J Pediatr 2002; 141: 51-58.

Newman S, Klinger L, Venn G, Smith P, Harrison M, Treasure T. Subjective reports of cognition in relation to assessed cognitive performance following coronary artery bypass surgery. J Psychosom Res 1989; 33: 227-233.

Nuutinen M, Koivu M, Rantakallio P. Long-term outcome for children with congenital heart defects. Arctic Medical Research 1989; 48: 175-184.

Oates RK, Simpson JM, Cartmill TB, Turnbull JAB. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child 1995; 72: 298-301.

O’Dougherty M, Berntson G, Boysen S, Wright FS, Teske D. Psycho-physiological predictors of attentional dysfunction in children with congenital heart defects. Psychophysiology 1988; 25: 305-315.

Pearson SR, Boyce TW. The vulnerable child syndrome. Pediatr Rev 2004; 25 (10): 345-349.

Sattler J. Assessment of children, 3rd edition. San Diego, CA: Author; 1992.

Scallan MJH. Brain injury in children with congenital heart disease. Paediatr Anesth 2003; 13: 284-293.


138 References

Spielberger CD, Edwards CD, Lushene RE, Montuori J, Platzek D. The State-Trait Anxiety Inventory for Children (prelimary manual). Palo Alto: Consulting Psychologists Press; 1973.

Timbremont B, Braet C. Children’s Depression Inventory, Manual, Dutch translation. Swets Test Publisher, Lisse, the Netherlands; 2002.

Towfighi J, Mauger D, Vannucci R, Vannucci S. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study. Dev Brain Res 1997; 100 (2): 149-160.

Ungerleider, R.M., Gaynor, J.W. The Boston Circulatory Arrest Study: An analysis. J Thorac Cardiovasc Surg 2004; 127: 1256-61.

Utens E, Verhulst FC, Meijboom FJ, Duivenvoorden HJ, Erdman RAM, Bos E, et al. Behavioral and emotional problems in children and adolescents with congenital heart disease Psychol Med 1993; 23: 415-424.

Utens E, Verhulst FC, Erdman RA, Meijboom FJ, Duivenvoorden HJ, Bos E, et al. Psychosocial functioning of young adults after surgical correction for congenital heart disease in childhood: a follow up study. J Psychosom Res 1994; 38: 745-758.

Van Rijen E, Utens E, Roos-Hesselink J, Meijboom FJ, van Domburg RT, Roelandt JR, et al. Psychosocial functioning in the adult with congenital heart disease: a 20-33 years follow-up. Eur Heart J 2003; 24: 673-683.

Van Rossum JH, Vermeer A. Competentiebelevingsschaal voor kinderen – Motorische Competentie- Zelfbeoordeling, Handleiding. Swets Test Publisher, Lisse, The Netherlands; 2000.

Veerman JW, Straathof MA, Treffers DA, Van den Bergh BRH, ten Brink LT. Competentiebelevingsschaal voor kinderen, Handleiding. Swets Test Publishers, Lisse, The Netherlands; 1997.

Verhulst FC, van der Ende J, Koot HM. Praktische handleiding voor de CBCL. Van Gorcum, Asse; 1990.

Visconti K, Bichell D, Jonas R, Newburger J, Bellinger D. Developmental outcome after surgical versus interventional closure of secundum atrial septal defect in children. Circulation 1999; 100 suppl II: 145-150.

Wray J, Sensky T. How does intervention of cardiac surgery affect the self-perception of children with congenital heart disease? Child Care Health Dev 1998; 24 (1): 57-72.

Wray J, Sensky T. Controlled study of preschool development after surgery for congenital heart disease. Arch Dis Child 1999; 80: 511-516.


References 139

Wray J, Sensky T. Congenital heart disease and cardiac surgery in childhood: effects on cognitive function and academic ability. Heart 2001; 85: 687-691.

Wright M, Nolan T. Impact of cyanotic heart disease on school performance. Arch Dis Child 1994; 71: 64-70.

Summary / Samenvatting/ Résumé 141

S u m m a r y / S a m e n v a t t i n g / R é s u m é


142 Summary / Samenvatting/ Résumé

S u m m ar y

Advances in surgical and medical treatment have resulted in an increasing number of children surviving with CHD. Despite the increased survival rates, morbidity remains a concern. It is documented that CHD is associated with impaired neurological and developmental functioning, but the mid-term functional outcome of children with CHD that underwent cardiac surgery remains to be determined. We examined the neuropsychological profile, behavior, emotions and self-perception of children with surgically corrected CHD 6 to 12 years postoperatively by comparing them to a healthy control group. In children with CHD, we identified a neuropsychological profile characterized by mainly mild motor deficits and subtle difficulties with language tasks. Attention/executive functioning and memory also appear involved, but to a lesser degree. Parents of CHD-children described their children to be less competent in school, having worse school performances and having a higher incidence of repeating a school year. On a cognitive questionnaire, parents of children with CHD more frequently report problems with attention, memory, and gross motor skills. Parental observations thus concur with most neuropsychological findings. Concerning behavior, parents reported social and attention problems as well as more aggressive behavior in their children. The children themselves did not rate their competence in school, social acceptance, sportive skills, motor functioning, physical appearance, behavior, or global self-worth to be different to that of healthy peers. They were not more anxious than peers, but did indicate more depressive symptoms. At school age, children with CHD display neuropsychological deficits on formal testing. This specification in the mid-term outcome profile of children with CHD, 6 to 12 years postoperatively, might lead to interventional programs, significantly improving functional outcome and quality of life. Further, this study endorses the usefulness of parental information since their observations concur with objectified measures. The cause of these functional deficits should be further elucidated incorporating preoperative, peri-operative, and postoperative variables. Possibly, a combination of several factors constitutes a child profile prone to adverse outcome. This study highlights the need for a multidisciplinary approach to follow-up of children with CHD, in order to provide correct referral as soon as possible, and interventional programs tailored to the needs of the child and its family.


Summary / Samenvatting/ Résumé 143

S a m e n v at t i n g

Door een enorme vooruitgang in de pediatrische hartheelkunde over de laatste 35 jaren, worden we geconfronteerd met een steeds groter wordende groep kinderen met een aangeboren hartafwijking (AHA). Ondanks de toegenomen overlevingskansen, blijft morbiditeit echter een grote zorg. Aangeboren hartafwijkingen worden immers geassocieerd met neurologische tekorten en een ontwikkelingsachterstand. De mid-term functionele status van het kind blijft tot hiertoe echter onbekend. We onderzochten het neuropsychologische profiel, het gedrag, de emotionele beleving en zelfperceptie van kinderen met een chirurgisch gecorrigeerde AHA 6 tot 12 jaar postoperatief door ze te vergelijken met een gezonde controlegroep. We weerhouden bij kinderen met een AHA een neuropsychologisch profiel dat voornamelijk milde motorisch tekorten vertoont alsook discrete taalproblemen. Aandacht -en executief functioneren, mede als het geheugen blijken, hoewel in mindere mate, eveneens betrokken. Ouders van kinderen met een AHA beschrijven hun kinderen als minder schoolbekwaam, ze halen minder goede schoolresultaten en het overdoen van een schooljaar komt meer voor in deze groep. Op een cognitieve klachtenlijst rapporteren de ouders van AHA kinderen meer aandacht- en geheugenproblemen, alsook een minder goede grove motoriek. Op gebied van gedrag vertonen deze kinderen volgens hun ouders meer sociale en aandachtsproblemen, en eveneens meer agressief gedrag. Uit zelfrapportering door de kinderen leiden we af dat er geen verschil is in het zelfconcept van de kinderen met AHA ten opzichte van gezonde controlekinderen op gebied van schoolse vaardigheden, sociale aanvaarding, sportieve vaardigheden en met name motoriek, uiterlijk, gedrag en zelfwaardering. Ze rapporteren geen verhoogde angst, maar wel meer depressieve symptomen dan gezonde controlekinderen. Deze beschrijving van de volledige functionele status van kinderen met een chirurgisch gecorrigeerde AHA 6 tot 12 jaar postoperatief, biedt mogelijkheden om gespecialiseerde interventies op te zetten aangepast aan de noden van het kind en de familie. Op deze manier kan de functionele status van het kind verbeteren. De oorzaak van deze functionele tekorten moet verder worden bestudeerd en moet zowel pre-, peri- als postoperatieve variabelen opnemen. Hoogst waarschijnlijk veroorzaakt een combinatie van factoren negatieve resultaten op langere termijn. De studie bekrachtigt ook het gebruik van ouderlijke vragenlijsten en wijst op de nood aan een multidisciplinaire aanpak van de follow-up van kinderen met een AHA. Enkel op deze manier kunnen problemen vroeg worden geïdentificeerd en aangepakt wat zal leiden tot een verbeterde levenskwaliteit bij kinderen met AHA.


144 Summary / Samenvatting/ Résumé

R é s um é

Grace aux progrès enormes, les enfants souffrant d’une cardiopathie congénitale (CC) et qui survivent à leur operation, deviennent de plus en plus nombreux. Malgré l’augmentation de la chance de survie, la mortalité reste préoccupante. Les cardiopathies congénitales sont associées à des déficits neurologiques et à un retard du développement. Pourtant, jusqu’ici, le fonctionnement cognitif, le comportement et les émotions des enfants avec CC restent inconnus. Nous avons examiné le profil neuropsychologique, le comportement, les émotions et l’image de soi des enfants souffrant d’une CC. Nous avons comparé leurs résultats avec ceux d’enfants en bonne santé. Le profil neuropsychologique est caractérisé par des troubles moteurs et des difficultés du langage. L’attention, la capacité à résoudre des problèmes et la mémoire sont également concernées, néanmoins à un degré moins élevé. Les parents des enfants présentant une CC considèrent leurs enfants comme moins capable à l’école, ils ont de mauvais résultats, plusieurs enfants parmi eux ont redouble leur année. Concernant les troubles cognitifs, les parents signalent plus de problèmes d’attention, de mémoire et de troubles moteurs. Par rapport à leur comportement, les enfants présentant une CC montrent plus de problèmes sociaux, plus de problèmes d’attention, et des comportements plus agressifs. Comparé avec des enfants en bonne santé, ils ne présentent pas de différence dans l’image de soi. Ils ne souffrent pas d’angoisse, mais les symptômes de dépression sont accrus. Cette description du profil neuropsychologique, du comportement, des émotions et de l’image de soi des enfants avec une CC permet la prescription d’interventions spécialisées, adaptées aux besoins de l’enfant et de sa famille. L’étude valide l’usage des questionnaires paternels et attire l’attention sur le fait qu’une approche multidisciplinaire est inévitable dans les soins postopératoires des enfants présentant une CC. C’est le meilleur moyen d’identifier les problèmes à temps et d’y remédier afin d’augmenter la qualité de vie de ceux-ci.

List of abbreviations 145

L i s t o f a b b r e v i a t i o n s ASD: atrial septal defect ASO: arterial switch operation AVC: atrioventricular canal CA: circulatory arrest CBCL: the Achenbach Child Behavior Checklist CDI: Children’s Depression Inventory CHD: congenital heart disease CICU: cardiac intensive care unit CPB: cardiopulmonary bypass DHCA: deep hypothermic circulatory arrest DORV: double outlet right ventricle ECC: extracorporeal circulation ECMO: extracorporeal membrane oxygenation FISH: fluorescence in situ hybridization HLHS: hypoplastic left heart syndrome IVS: intact ventricular septum LFB: low flow bypass NEPSY: a developmental neuropsychological assessment NYHA-class: New York Heart Association Class – modified NYUPHFI: New York University pediatric heart failure index PDA: patent ductus arteriosus PVL: periventricular leukomalacia SD: standard deviation SPP-C: Self-perception profile for Children SPSS: statistical package for social sciences


146 List of abbreviations

STAI-C: the State- Trait Anxiety Inventory for Children TGA: transposition of the great arteries TOF: tetralogy of Fallot VSD: ventricular septal defect WAIS:Wechsler Adult Intelligence Scale WeeFIM: Functional Independence measure for Children WISC-III-NL: Wechsler Intelligence Scale for Children- 3rd edition- Dutch version WPPSI-R: Wechsler Preschool and Primary Scale of Intelligence- Revised WRAT : Wide Range Achievement Test WRAVMA : Wide Range Assessment of Visual Motor Abilities

Appendix 147

A p p e n d i x


148 Appendix

Klachtenlijst

In deze klachtenlijst worden u enkele vragen gesteld met betrekking tot de cognitieve en emotionele toestand van uw kind. Lees aandachtig elke vraag en onderstreep of omcirkel het antwoord dat het best bij jullie kind past. A. COGNITIEVE DIMENSIE 1 Volgehouden aandacht 1.1. Mijn kind heeft moeite om zijn/haar aandacht langdurig op iets (bv.

studeren, spel, TV, ...) gevestigd te houden.

altijd / meestal / soms / nooit 1.2.1 Mijn kind heeft het moeilijk om een mentale inspanning (bv. studeren)

langere tijd vol te houden.

altijd / meestal / soms / nooit 1.2.2 Mijn kind moet, vaker dan leeftijdsgenootjes, taken langzamer doen om ze

goed te kunnen doen.

altijd / meestal / soms / nooit

2 Verdeelde aandacht 2.1 Mijn kind kan moeilijk twee dingen tegelijk doen.

altijd / meestal / soms / nooit 2.2 Mijn kind is snel afleidbaar



Appendix 149

2.3 Mijn kind reageert minder snel dan leeftijdsgenootjes op wat er rondom hem of haar gezegd of gedaan wordt.


3 Geheugen 3.1 Mijn kind is vergeetachtig (bv. vergeet huiswerkopdrachten, turn/

zwemmateriaal)


3.2 Mijn kind kan zich bepaalde dingen niet meer herinneren (bepaalde gebeurtenissen, gegeven opdrachten)


3.3 Mijn kind kan moeilijk nieuwe informatie (bv. lesinhoud) aanleren en/of

onthouden


4 Probleemoplossend gedrag 4.1 Mijn kind kan moeilijk activiteiten plannen (geraakt snel in de knoei)

altijd / meestal / soms / nooit 4.2 Mijn kind kan moeilijk beslissingen nemen

altijd / meestal / soms / nooit 4.3 Bij een taak die bestaat uit meerdere stappen, heeft mijn kind moeite met de

juiste volgorde

altijd / meestal / soms / nooit 5 Motoriek


150 Appendix

5.1 Het geschrift van mijn kind is slordiger/ minder duidelijk dan dat van

leeftijdsgenootjes


5.2 Mijn kind heeft het moeilijk met fijn motorische taken (knippen, kralen rijgen, schrijven, inkleuren, enz.)


5.3 Mijn kind heeft het motorisch moeilijker met lichamelijke activiteiten

(zwemmen, lopen, turnen) dan leeftijdsgenootjes

altijd / meestal / soms / nooit B. EMOTIONELE DIMENSIE 1. Emotionele stabiliteit 1.1 Mijn kind is prikkelbaar/opvliegend

altijd / meestal / soms / nooit 1.2 Mijn kind heeft last van stemmingswisselingen

altijd / meestal / soms / nooit 1.3 Mijn kind is neerslachtig, verdrietig

altijd / meestal / soms / nooit 2. Angst 2.1 Mijn kind is over het algemeen angstig (schrikachtig, op zijn/haar hoede)

altijd / meestal / soms / nooit 2.2 Mijn kind piekert/denkt veel na over zijn/haar gezondheid


Appendix 151


2.3 Mijn kind is rusteloos

altijd / meestal / soms / nooit 2.4 Mijn kind heeft last van slaapproblemen


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NEUROPSYCHOLOGICAL FUNCTIONING IN CHILDREN WITH A … · Table of Contents i Table of contents Dankwoord iii Chapter 1 Introduction 1 1.1 General introduction 3 1.2 Neurocognitive