Publications by authors named "Michael von Rhein"

21 Publications

  • Page 1 of 1

The Coping with and Caring for Infants with Special Needs intervention was associated with improved motor development in preterm infants.

Acta Paediatr 2020 Oct 12. Epub 2020 Oct 12.

University of Groningen, University Medical Center Groningen, Department of Pediatrics, Division of Developmental Neurology, Groningen, The Netherlands.

Aim: We compared the impact of standard infant physiotherapy and the family-centred programme, Coping with and Caring for Infants with Special Needs (COPCA), in infants born before 32 weeks without significant brain lesions.

Methods: This randomised controlled trial was carried out in patients' homes and outpatient settings in Switzerland between January 2016 and October 2019. We used data from the national SwissNeoNet register and an assessment battery that included infant and family outcomes and video analyses of therapy sessions. The Infant Motor Profile was the primary outcome instrument.

Results: The COPCA group comprised six boys and two girls with a median gestational age of 27 weeks (range 25-30), and the standard care group comprised seven boys and one girl with a median gestational age of 29.5 weeks (range 26-31). COPCA participants improved significantly more between baseline and 18 months in the IMP variation (9.0 percentage points, 95% confidence interval: 0.3-17.5) and performance (12.0 percentage points, 95% confidence interval: 4.1-20.6) domains than standard care participants. COPCA coaching was positively associated with IMP scores at 18 months, but some standard care actions were negatively associated.

Conclusion: COPCA was associated with better motor outcome in infants born before 32 weeks than standard infant physiotherapy.
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http://dx.doi.org/10.1111/apa.15619DOI Listing
October 2020

Altered frontal white matter microstructure is associated with working memory impairments in adolescents with congenital heart disease: A diffusion tensor imaging study.

Neuroimage Clin 2020 16;25:102123. Epub 2019 Dec 16.

Children's Research Center, University Children's Hospital Zurich, Switzerland; Center for MR Research, University Children's Hospital Zurich, Switzerland. Electronic address:

Children and adolescents with congenital heart disease (CHD) are at risk for mild to moderate cognitive impairments. In particular, impaired working memory performance has been found in CHD patients of all ages. Working memory is an important domain of higher order cognitive function and is crucial for everyday activities, with emerging importance in adolescence. However, the underlying neural correlate of working memory impairments in CHD is not yet fully understood. Diffusion tensor imaging and tract based spatial statistics analyses were conducted in 47 adolescent survivors of childhood cardiopulmonary bypass surgery (24 females) and in 44 healthy controls (24 females) between 11 and 16 years of age (mean age = 13.9, SD = 1.6). Fractional anisotropy (FA) of white matter diffusion was compared between groups and was correlated with working memory performance, derived from the Wechsler Intelligence Scale for Children-IV. CHD patients had significantly poorer working memory compared to controls (p = 0.001). Widespread bilateral reduction in FA was observed in CHD patients compared to healthy controls (threshold-free cluster enhancement (TFCE) corrected p < 0.05). This reduction in FA was present both in cyanotic and acyanotic CHD patients compared to healthy controls (both p < 0.001). The FA reduction in the frontal lobe, mainly in the forceps minor, was associated with poorer working memory performance in both patients with CHD and healthy controls (TFCE corrected p < 0.05). The current findings underline that in CHD patients, irrespective of disease severity, disrupted or delayed maturation of white matter may persist into adolescence and is associated with working memory impairments, particularly if present in the frontal lobe. Adolescence, which is a crucial period for prefrontal brain maturation, may offer a window of opportunity for intervention in order to support the maturation of frontal brain regions and therefore improve higher order cognitive function in patients with CHD.
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http://dx.doi.org/10.1016/j.nicl.2019.102123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933217PMC
December 2020

Pitfalls of using IQ short forms in neurodevelopmental disorders: a study in patients with congenital heart disease.

Pediatr Res 2020 04 11;87(5):917-923. Epub 2019 Nov 11.

Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.

Background: Short forms of IQ (S-IQ) assessments are time efficient and highly predictive of the full IQ (F-IQ) in healthy individuals. To investigate the validity of S-IQs for patients with neurodevelopmental impairments, this study tested a well-established S-IQ version in patients with congenital heart disease (CHD).

Methods: The Wechsler Intelligence Scale for Children, Fourth Edition was applied in 107 children with complex CHD aged 9-11 years. F-IQ and a well-established S-IQ version were calculated for each patient. The agreement between S-IQ and F-IQ was investigated across the whole spectrum of IQ scores. Finally, we tested a method to adjust IQs to resolve potential bias and validated this method in an independent sample of 55 CHD patients.

Results: S-IQ and F-IQ correlated strongly. Nevertheless, the size of the bias correlated with the true IQ, indicating larger error at the tails of the distribution. Estimating a corrected IQ by adjusting the S-IQ with correction parameters substantially improved agreement.

Conclusion: We here report that substantial bias may underestimate low IQ scores and overestimate high ones. This bias should be considered when at-risk populations are assessed with S-IQs. Importantly, the bias can be minimized by using a correction formula.
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http://dx.doi.org/10.1038/s41390-019-0667-2DOI Listing
April 2020

Postoperative brain volumes are associated with one-year neurodevelopmental outcome in children with severe congenital heart disease.

Sci Rep 2019 07 26;9(1):10885. Epub 2019 Jul 26.

Children's Research Centre, University Children's Hospital Zurich, Zürich, Switzerland.

Children with congenital heart disease (CHD) remain at risk for neurodevelopmental impairment despite improved perioperative care. Our prospective cohort study aimed to determine the relationship between perioperative brain volumes and neurodevelopmental outcome in neonates with severe CHD. Pre- and postoperative cerebral MRI was acquired in term born neonates with CHD undergoing neonatal cardiopulmonary bypass surgery. Brain volumes were measured using an atlas prior-based automated method. One-year neurodevelopmental outcome was assessed with the Bayley-III. CHD infants (n = 77) had lower pre- and postoperative total and regional brain volumes compared to controls (n = 44, all p < 0.01). CHD infants had poorer cognitive and motor outcome (p ≤ 0.0001) and a trend towards lower language composite score compared to controls (p = 0.06). Larger total and selected regional postoperative brain volumes were found to be associated with better cognitive and language outcomes (all p < 0.04) at one year. This association was independent of length of intensive care unit stay for total, cortical, temporal, frontal and cerebellar volumes. Therefore, reduced cerebral volume in CHD neonates undergoing bypass surgery may serve as a biomarker for impaired outcome.
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http://dx.doi.org/10.1038/s41598-019-47328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659678PMC
July 2019

Left temporal plane growth predicts language development in newborns with congenital heart disease.

Brain 2019 05;142(5):1270-1281

Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Congenital heart defects are the most common congenital anomalies, accounting for a third of all congenital anomaly cases. While surgical correction dramatically improved survival rates, the lag behind normal neurodevelopment appears to persist. Deficits in higher cognitive functions are particularly common, including developmental delay in communication and oral-motor apraxia. It remains unclear whether the varying degree of cognitive developmental delay is reflected in variability in brain growth patterns. To answer this question, we aimed to investigate whether the rate of regional brain growth is correlated with later life neurodevelopment. Forty-four newborns were included in our study, of whom 33 were diagnosed with dextro-transposition of the great arteries and 11 with other forms of severe congenital heart defects. During the first month of life, neonates underwent corrective or palliative cardiovascular bypass surgery, pre- and postoperative cerebral MRI were performed 18.7 ± 7.03 days apart. MRI was performed in natural sleep on a 3.0 T scanner using an 8-channel head coil, fast spin-echo T2-weighted anatomical sequences were acquired in three planes. Based on the principles of deformation-based morphometry, we calculated brain growth rate maps reflecting average daily growth occurring between pre- and postoperative brain images. An explorative, whole-brain, threshold-free cluster enhancement analysis revealed strong correlation between the growth rate of the Heschl's gyrus, anterior planum temporale and language score at 12 months of age, corrected for demographic variables (P = 0.018, t = 5.656). No significant correlation was found between brain growth rates and motor or cognitive scores. Post hoc analysis showed that the length of hospitalization interacted with this correlation, longer hospitalization resulted in faster enlargement of the internal CSF spaces. Our longitudinal cohort study provides evidence for the early importance of left-dominant perisylvian regions in auditory and language development before direct postnatal exposure to native language. In congenital heart disease patients, the perioperative period results in a critical variability of brain growth rate in this region, which is a reliable neural correlate of language development at 1 year of age.
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http://dx.doi.org/10.1093/brain/awz067DOI Listing
May 2019

Population based report on health related quality of life in adolescents born very preterm.

Early Hum Dev 2017 01 6;104:7-12. Epub 2016 Dec 6.

Department of Neonatology, Zurich University Hospital, Frauenklinikstrasse 10, 8091 Zurich, Switzerland.

Background: As the survival rate of preterm infants constantly improves, knowledge on the impact of prematurity on long-term health-related quality of life (HRQoL) is important for clinical and parental guidance. We aimed to assess HRQoL in a national cohort of young adolescents born very preterm, and to identify predictors for poorer HRQoL.

Patients And Methods: All surviving Swiss live-born children below 30weeks of gestation during the year 2000 (290 subjects) were contacted at age 12years, together with their parents (262 families). HRQoL of the study children was assessed using both the Kidscreen-27 (KS-27) self- and parent forms. Neonatal data of the cohort were prospectively collected.

Results: Among the contacted families, 176 returned the complete set of questionnaires for 194 adolescents (67%): 100 (51%) females, mean (range) gestational age was 27.8 (24.1-29.9) weeks, birth weight 1025 (420-1730) grams, mean age at assessment 12.0 (11.0-13.0) years. Included children had similar neonatal and socio-demographic characteristics as non-responders. Average self- and parent-reported HRQoL of former preterms was similar to Swiss KS-27 norms. According to the multivariable models (r=0.2), surgical closure of patent ductus arteriosus, attention deficit/hyperactivity disorder, severe neurodevelopment impairment were negatively associated with both self- and parent-reported HRQoL.

Conclusions: HRQoL in this population-based cohort of adolescents born very preterm is good. Surgical closure of patent ductus arteriosus, attention deficit/hyperactivity disorder, severe neurodevelopment impairment were identified as predictors of poorer HRQoL using multivariable models, explaining however only a low proportion of variance in HRQoL.
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http://dx.doi.org/10.1016/j.earlhumdev.2016.11.002DOI Listing
January 2017

Delayed cortical gray matter development in neonates with severe congenital heart disease.

Pediatr Res 2016 11 19;80(5):668-674. Epub 2016 Jul 19.

Child Development Center, University Children´s Hospital Zurich, Switzerland.

Background: This study aimed to assess cortical gray matter growth and maturation in neonates with congenital heart disease (CHD).

Methods: Thirty-one (near) term neonates with severe CHD (8 univentricular heart malformation (UVH), 21 d-transposition of great arteries (d-TGA) and 2 aortic coarctation) underwent cerebral MRI before (postnatal-day 7) and after (postnatal-day 24) surgery. Eighteen controls with similar gestational age had one MRI (postnatal-day 23). Cortical gray matter volume (CGM), inner cortical surface (iCS), and median cortical thickness were extracted as measures of volumetric growth, and gyrification index (GI) as measure of maturation.

Results: Over a median of 18 d, CGM increased by 21%, iCS by 17%, thickness and GI both by 9%. Decreased postoperative CGM and iCS were seen for CHD compared to controls (P values < 0.01), however with similar thickness and GI. UVH showed lower postoperative iCS, thickness (P values < 0.05) and GI (P value < 0.01) than d-TGA and controls. Infants requiring preoperative balloon-atrioseptostomy (BAS, 61%) had reduced postoperative CGM, iCS, and GI (P values < 0.05).

Conclusion: Infants with severe CHD show reduced cortical volumes compared to controls with gyrification being delayed in UVH, but not in d-TGA. Infants requiring BAS show higher risk of impaired cortical volume and gyrification.
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http://dx.doi.org/10.1038/pr.2016.145DOI Listing
November 2016

Comparison of automated brain volumetry methods with stereology in children aged 2 to 3 years.

Neuroradiology 2016 Sep 5;58(9):901-10. Epub 2016 Jul 5.

Center for MR Research, University Children's Hospital of Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.

Introduction: The accurate and precise measurement of brain volumes in young children is important for early identification of children with reduced brain volumes and an increased risk for neurodevelopmental impairment. Brain volumes can be measured from cerebral MRI (cMRI), but most neuroimaging tools used for cerebral segmentation and volumetry were developed for use in adults and have not been validated in infants or young children. Here, we investigate the feasibility and accuracy of three automated software methods (i.e., SPM, FSL, and FreeSurfer) for brain volumetry in young children and compare the measures with corresponding volumes obtained using the Cavalieri method of modern design stereology.

Methods: Cerebral MRI data were collected from 21 children with a complex congenital heart disease (CHD) before Fontan procedure, at a median age of 27 months (range 20.9-42.4 months). Data were segmented with SPM, FSL, and FreeSurfer, and total intracranial volume (ICV) and total brain volume (TBV) were compared with corresponding measures obtained using the Cavalieri method.

Results: Agreement between the estimated brain volumes (ICV and TBV) relative to the gold standard stereological volumes was strongest for FreeSurfer (p < 0.001) and moderate for SPM segment (ICV p = 0.05; TBV p = 0.006). No significant association was evident between ICV and TBV obtained using SPM NewSegment and FSL FAST and the corresponding stereological volumes.

Conclusions: FreeSurfer provides an accurate method for measuring brain volumes in young children, even in the presence of structural brain abnormalities.
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http://dx.doi.org/10.1007/s00234-016-1714-xDOI Listing
September 2016

Hippocampal volume reduction is associated with intellectual functions in adolescents with congenital heart disease.

Pediatr Res 2016 10 6;80(4):531-7. Epub 2016 Jun 6.

Child Development Center, University Children's Hospital, Zurich, Switzerland.

Background: Adolescents undergoing early cardiopulmonary bypass surgery for congenital heart disease (CHD) may demonstrate a variety of neurocognitive impairments. These impairments can affect overall intellectual functions, but also specific memory deficits, language, and executive functions. As the hippocampus is a critical structure involved in these functions, we sought to determine whether hippocampal volume was reduced in adolescents with CHD and whether altered volumes were related to functional outcome.

Methods: At a mean age of 13.8 y, 48 adolescent survivors of childhood cardiopulmonary bypass surgery for CHD and 32 healthy controls underwent neurocognitive testing and cerebral magnetic resonance imaging. Images were quantitatively analyzed using an automated regional segmentation tool (FSL-FIRST).

Results: Adolescents with CHD had 10% lower total hippocampal volumes compared with controls. After controlling for total brain volume, total hippocampal volume correlated with total IQ, with working memory, and verbal comprehension in CHD patients, but not in controls.

Conclusions: In adolescent survivors of cardiopulmonary bypass surgery for CHD, specific brain regions such as the hippocampus may show long-term persistent alteration and correlate with intellectual deficits, particularly with verbal and memory functions.
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http://dx.doi.org/10.1038/pr.2016.122DOI Listing
October 2016

Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes.

J Pediatr 2015 Dec 29;167(6):1259-63.e1. Epub 2015 Jul 29.

Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Objectives: To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth.

Study Design: Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions.

Results: Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001).

Conclusions: Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth.
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http://dx.doi.org/10.1016/j.jpeds.2015.07.006DOI Listing
December 2015

Persistence of visuo-constructional and executive deficits in adolescents after open-heart surgery.

Res Dev Disabil 2015 01 4;36C:303-310. Epub 2014 Nov 4.

Department of Psychiatry and Psychotherapy A, General Hospital, Milser Straße 10, 6060 Hall in Tyrol, Austria.

Aim: This study assesses whether previously reported performance deficiencies in visuo-constructional and executive functions, using the Rey-Osterrieth Complex Figure Test (ROCFT) in pediatric patients with congenital heart disease (CHD), persist into adolescence.

Methods: 53 adolescent CHD patients (mean age 13.7) and 39 healthy controls (mean age 14.1) participated. ROCFT performance was measured by three different scoring methods, focusing either on quantitative (Meyers & Meyers, 1995), qualitative (Wallon & Mesmin, 2009), or both performance aspects (Bernstein & Waber, 1996). Potential confounders (i.e., intelligence and visuomotor integration) and surgery-related risk factors were included in the data analysis.

Results: Adolescents with CHD demonstrated immature copy and recall approaches on the ROCFT using the qualitative system by Wallon and Mesmin (p<.001). Memory performance was also predicted by Bernstein and Waber scores (p<.03), whereas group differences were not significant according to the other scoring methods. Intelligence and visuomotor skills, but not surgery-related risk factors, were positively correlated with ROCFT performance (each p<.02). Interpretation: Visuoconstructional and executive deficiencies could be found in adolescent patients with CHD. However, not all ROCFT scoring methods were equally apt to detect group differences: especially the qualitative scoring method developed by Wallon and Mesmin seems sufficiently sensitive to detect long-lasting visuo-constructional and executive deficiencies in CHD patients.
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http://dx.doi.org/10.1016/j.ridd.2014.10.027DOI Listing
January 2015

Clinical course and interstage monitoring after the Norwood and hybrid procedures for hypoplastic left heart syndrome.

Pediatr Cardiol 2014 Jun 18;35(5):851-6. Epub 2014 Jan 18.

Division of Pediatric Cardiology, University Children's Hospital, Steinwiesstrasse 75, 8032, Zurich, Switzerland,

Infants with hypoplastic left heart syndrome (HLHS) are at risk for interstage morbidity and mortality, especially between the first and second surgical stages after the Norwood and hybrid procedures. This study compared the morbidity and mortality of patients treated by either the Norwood or the hybrid procedure for HLHS between the first and second stages who were undergoing interstage monitoring. Between October 2008 and December 2011, 26 infants (14 boys) with HLHS (n = 16) and other univentricular heart malformations with aortic arch anomaly (n = 10) were scheduled for interstage monitoring after Norwood I (n = 12) and hybrid (n = 14) procedures. Three infants (11.5 %) died after first-stage palliation (one hybrid patient and two Norwood patients), and three infants (11.5 %) died after second-stage palliation (two hybrid patients and one Norwood patient) (p = 0.83), all after early second-stage surgery (<90 days). The Norwood I and hybrid procedures did not differ in terms of overall mortality (23 %) (three hybrid and three Norwood patients; p = 1.00). Seven infants (26.9 %) could not be discharged from the hospital due to hemodynamic instability and were referred for early second-stage surgery (<90 days). After the first stage, the invasive reevaluation rate before discharge was high (53.8 %), with cardiac catheterizations for 8 of 14 patients after the hybrid procedure and for 6 of 12 patients after the Norwood procedure (p = 0.69). A total of 11 reinterventions were performed (eight by catheter and three by surgery). Of the eight catheter reinterventions, five were performed for hybrid patients (p = 0.22). For 14 infants, 89 days (range 10-177 days) of interstage monitoring were scheduled. One infant (3.9 %) died during the interstage monitoring. The findings showed a breach of the physiologic criteria for interstage monitoring in seven infants (50 %) after 10 days (range 4-68 days) (five hybrid and two Norwood patients), leading to rehospitalization and catheterization for six patients (four hybrid and two Norwood patients), requiring interventions for two patients (patent arterial duct stent dilation, and atrial septal defect stenting, all for hybrid patients). Overall, three of the seven patients with red flag events of interstage monitoring were candidates for early second-stage surgery. In conclusion, morbidity among infants treated for HLHS remains high, either before or after hospital discharge, emphasizing the need of interstage monitoring programs. Despite retrograde aortic flow in infants with HLHS after the hybrid procedure, the mortality rate was comparable between the two groups. Mortality occurs after early second-stage surgery (<90 days).
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http://dx.doi.org/10.1007/s00246-014-0865-yDOI Listing
June 2014

Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease.

Brain 2014 Jan 25;137(Pt 1):268-76. Epub 2013 Nov 25.

1 Child Development Centre, University Children's Hospital, Zurich, Switzerland.

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.
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http://dx.doi.org/10.1093/brain/awt322DOI Listing
January 2014

[Developmental disorders in preschool children: an interdisciplinary approach].

Ther Umsch 2013 Nov;70(11):637-45

Abteilung Entwicklungspädiatrie, Kinderspital Zürich und Sozialpädiatrisches Zentrum, Kantonsspital Winterthur.

Many children show developmental abnormalities in the first years of life. Thus, the primary care physician should know the procedures of developmental surveillance and screening and be informed about the further steps in the evaluation of children with developmental disorders. This article presents current developmental screening methods in primary care, defines the terminology of developmental disorders in young children, demonstrates the essential diagnostic procedures in developmentally impaired children and describes the interdisciplinary collaboration between physicians, psychologists, therapists and special needs educators.
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http://dx.doi.org/10.1024/0040-5930/a000459DOI Listing
November 2013

Cerebral lesions on magnetic resonance imaging correlate with preoperative neurological status in neonates undergoing cardiopulmonary bypass surgery.

Eur J Cardiothorac Surg 2014 Apr 12;45(4):625-32. Epub 2013 Sep 12.

Pediatric Cardiology, University Children's Hospital, Zurich, Switzerland.

Objectives: To determine the prevalence, spectrum and course of cerebral lesions in neonates with congenital heart disease (CHD) undergoing full flow cardiopulmonary bypass (CPB) surgery using magnetic resonance imaging (MRI) and to examine the correlation between cerebral lesions and clinical neurological abnormalities.

Methods: Prospective cohort study of neonates with d-transposition of the great arteries (n = 22), univentricular heart malformation with hypoplastic aortic arch (n = 6) and aortic arch obstructions (n = 2) undergoing CPB. Neonates underwent cerebral MRI and blinded standardized neurological examination before (median day 6) and after surgery (day 13). The MRI findings were compared with those of 20 healthy controls.

Results: Preoperative cerebral lesions were present in 7 of 30 patients (23%) with isolated mild or moderate white matter injury (WMI) (n = 4), isolated small cerebral stroke (n = 1) and combined WMI and stroke (n = 2). None of the healthy controls had cerebral lesions on MRI. CHD neonates with preoperative cerebral lesions had more neurological abnormalities (P = 0.01) than neonates without cerebral lesions. Low arterial oxygen saturation (P = 0.03) was a risk factor for preoperative cerebral lesions, while balloon atrioseptostomy (P = 0.19) was not. After surgery, preoperative cerebral lesions persisted in 5 of 7 neonates, and 2 neonates (7%) showed signs of additional WMI in their postoperative MRI.

Conclusions: In neonates with severe CHD, WMI was the predominant preoperative finding, while cerebral strokes were less frequent. New postoperative lesions were rare. Preoperative neurological abnormalities correlated with the presence of cerebral lesions on MRI.
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http://dx.doi.org/10.1093/ejcts/ezt422DOI Listing
April 2014

Neurodevelopmental outcome, psychological adjustment, and quality of life in adolescents with congenital heart disease.

Dev Med Child Neurol 2013 Dec 13;55(12):1143-9. Epub 2013 Aug 13.

Child Development Centre, University Children's Hospital Zurich, Zurich, Switzerland.

Aim: The aim of this study was to examine neurodevelopment, psychological adjustment, and health-related quality of life (HRQoL) in adolescents after bypass surgery for congenital heart disease (CHD) during early childhood.

Method: Fifty-nine adolescents (34 females, 25 males) with CHD were examined at a median age of 13 years 8 months (range 11 y 5 mo-16 y 11 mo). Outcome was assessed with the Wechsler Intelligence Scale for Children, (fourth edition); the Beery Test of Visual-Motor Integration; the Rey-Osterrieth Complex Figure Test; the Zurich Neuromotor Assessment; the Strengths and Difficulties Questionnaire; and the KIDSCREEN questionnaires. Results were compared with those of 40 age- and sex-matched healthy comparison individuals.

Results: Outcome with regard to full-scale IQ, perceptual reasoning, and the working memory scale was poorer in patients with CHD than in the comparison group (all p ≤ 0.001). Visual perception, visuomotor integration (p ≤ 0.001), and executive functions (Rey figure copy: p=0.05) were also affected. Patients with CHD also had lower scores on all motor domains (p < 0.02) except static balance. Psychological adjustment was affected only in the 'peer relationship' domain (p=0.05). Quality of life was similar to that of typically developing peers.

Interpretation: Adolescents with CHD may manifest persistent cognitive and motor impairments, while psychological adjustment and self-reported HRQoL are mostly typical. Thus, long-term neurodevelopmental evaluations are necessary to provide early educational and therapeutic support.
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http://dx.doi.org/10.1111/dmcn.12242DOI Listing
December 2013

Risk factors for neurodevelopmental impairments in school-age children after cardiac surgery with full-flow cardiopulmonary bypass.

J Thorac Cardiovasc Surg 2012 Sep 9;144(3):577-83. Epub 2012 Mar 9.

Child Development Center, Children's Hospital, Zurich, Switzerland.

Objective: To determine the risk factors for adverse neurodevelopmental outcomes in school-age children after full flow open-heart surgery for congenital heart disease.

Methods: The outcome was assessed in 117 children without a genetic comorbidity at a mean age of 10.4 ± 2.5 years. Intelligence was assessed using the Raven's Progressive Matrices and neuromotor function using the Zurich Neuromotor Assessment. Risk factors were retrieved from detailed chart review.

Results: The mean intelligence score was 89 ± 16, significantly lower than the norm (P < .001). Cerebral palsy was diagnosed in 10% of patients. Poor neuromotor performance (less than p10) was present in 15% to 20% of the children, depending on the motor task (all P < .001). Pure motor and static balance performance was also significantly impaired when patients with cerebral palsy were excluded (P < .01). Intelligence was only related to socioeconomic status (P = .006), and neuromotor outcome was related to the length of hospital stay and postoperative neurologic abnormalities (P < .03). The extracorporeal circulation time was related to adaptive fine motor performance (P = .05). All other variables were not related to outcome.

Conclusions: Children without a genetic comorbidity are at risk of long-term intellectual and motor impairments also after full-flow cardiac repair. Surgery-related parameters play a less important role for adverse outcomes than postoperative complications. Our findings stress the importance of specialized follow-up assessments for all children with CHD undergoing open heart surgery.
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http://dx.doi.org/10.1016/j.jtcvs.2012.02.005DOI Listing
September 2012

Mortality and neurodevelopmental outcome at 1 year of age comparing hybrid and Norwood procedures.

Eur J Cardiothorac Surg 2012 Jul 18;42(1):33-9. Epub 2012 Jan 18.

Division of Paediatric Cardiology, University Children's Hospital Zurich, Zurich, Switzerland.

Objectives: Neonates with hypoplastic left heart syndrome (HLHS) are at risk of high mortality and neurodevelopmental morbidity. As an alternative to Norwood-type stage I palliation, the hybrid procedure has been developed. It consists of bilateral pulmonary artery banding, catheter-based stenting of the arterial duct and balloon atrioseptostomy and delays open-heart surgery. Thus, it may be associated with a better outcome. The aim of this study was to determine the mortality and neurodevelopmental outcome in patients with HLHS and other univentricular heart (UVH) defects treated with hybrid or Norwood procedures.

Methods: Thirty-one children (18 males) with HLHS and other UVH defects undergoing Norwood or hybrid procedure between 2004 and 2008 were consecutively enrolled. Mortality and neurodevelopmental outcome at 1 year of age were determined.

Results: One-year mortality was 36% (31% in the hybrid vs. 39% in the Norwood group, P=0.71). Predictors of mortality were lower birth weight (P=0.02), older age at first procedure (P=0.02) and smaller size of ascending aorta (P=0.05). Overall, median psychomotor development index (PDI) and mental development index (MDI) of the Bayley Scales of Infant Development II were lower than the norm of 100 [PDI 57 (49-99), P<0.001; MDI 91 (65-109), P=0.002]. No effect of surgical treatment on neurodevelopmental outcome was found. Predictors of impaired motor outcome were length of hospital stay (LOHS) (P=0.01), lower body weight at second procedure (P=0.004) and female sex (P=0.01). Predictors of impaired cognitive outcome were longer mechanical ventilation time (P=0.03), intensive care unit stay (P=0.04) and LOHS (P<0.001), respectively.

Conclusions: Mortality at 1 year of age is comparable between patients undergoing hybrid and Norwood procedures. Early neurodevelopmental outcome is significantly impaired in patients with both HLHS and other UVH defects. Multicentre randomized studies are needed to determine the long-term neurodevelopmental outcome of children treated with the hybrid procedure.
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http://dx.doi.org/10.1093/ejcts/ezr286DOI Listing
July 2012

Structural brain lesions in adolescents with congenital heart disease.

J Pediatr 2011 Jun 14;158(6):984-9. Epub 2011 Jan 14.

Child Development Center, University Children's Hospital, Zurich, Switzerland.

Objectives: To assess long-term neurodevelopmental outcome of adolescents with congenital heart disease after open-heart surgery and to evaluate whether deficits are associated with cerebral injury detectable on magnetic resonance imaging (MRI).

Study Design: We conducted a cohort study with longitudinal follow-up of 53 adolescents (mean age, 13.7 years; range, 11.4 to 16.9 years) who had undergone open-heart surgery with full-flow cardiopulmonary bypass during childhood and compared them with 41 age-matched controls. Assessment included conventional MRI and neurodevelopmental testing.

Results: MRI abnormalities were detected in 11 of the 53 patients (21%), comprising predominately white matter abnormalities and volume loss. Neurodevelopmental outcome was impaired in several domains, including neuromotor, intellectual, and executive functions, as well as visuomotor perception and integration. Adolescents with cerebral abnormalities had greater impairment in most neurodevelopmental domains compared with those without cerebral abnormalities.

Conclusions: Cerebral abnormalities can be detected in a significant proportion of adolescents with corrected congenital heart disease. These abnormalities are found predominately in the white matter and are apparently of hypoxic-ischemic origin, most likely acquired during the neonatal period.
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http://dx.doi.org/10.1016/j.jpeds.2010.11.040DOI Listing
June 2011

Significance of patient categorization for perioperative management of children with tetralogy of Fallot, with special regard to co-existing malformations.

Cardiol J 2010 ;17(1):20-8

University of Mainz, Children's Hospital, Mainz, Germany.

Background: The aim of our study was to facilitate perioperative calculation of potential risk factors on the outcome of corrective surgery for children with tetralogy of Fallot.

Methods: The medical records of 81 (44 female and 37 male) out of a total of 87 patients undergoing complete surgical repair of tetralogy of Fallot between 1988 and 2004 at the Children's Hospital of the Johannes Gutenberg University of Mainz were reviewed. PATIENTS were divided into four categories, depending on the severity of pulmonary stenosis and cyanosis, as well as on the type of pulmonary circulation.

Results: Additional malformations did not affect mortality rates, but did directly affect the number of pleural effusions, time of epinephrine administration, duration of surgery, bypass, and ischemia, as well as length of hospitalization and intensive care unit treatment. In contrast to longer periods of extracorporeal circulation and ischemia during surgery, which are directly related not only to more complex anatomical situations but also to higher mortality and complication rates, the much-debated question of age at surgery had no influence either on the surgical approach itself or on the post-operative outcome.

Conclusions: Our patient categorization, and evaluation of potential pre-operative risk factors and intraoperative parameters, should prove useful for the future planning and execution of therapeutic procedures in institutions around the world.
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April 2010

Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.

Am J Hum Genet 2008 Jan;82(1):188-93

Department of Obstetrics and Gynecology, Technical University Munich, 81675 Munich, Germany.

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.
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http://dx.doi.org/10.1016/j.ajhg.2007.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253959PMC
January 2008