Publications by authors named "Paul Govaert"

86 Publications

Motor outcome after perinatal stroke and early prediction of unilateral spastic cerebral palsy.

Eur J Paediatr Neurol 2020 Nov 21;29:54-61. Epub 2020 Sep 21.

Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium.

Background: Unilateral spastic cerebral palsy (USCP) occurs in 30%-68% of infants with perinatal stroke. Early detection of USCP is essential for referring infants to early intervention. The aims of this study were to report motor outcomes after perinatal stroke, and to determine the predictive value of the General Movements Assessment (GMA) and Hand Assessment for Infants (HAI) for detection of USCP.

Materials And Methods: This was a prospective observational study involving infants with perinatal stroke. GMA was conducted between 10 and 15 weeks post term-age (PTA). The HAI was performed between 3 and 5 months PTA. Motor outcome was collected between 12 and 36 months PTA.

Results: The sample consisted of 46 infants. Fifteen children (32.6%) were diagnosed with CP, two children with bilateral CP and 13 with USCP. Abnormal GMA had a sensitivity of 85% (95% confidence interval [CI] 55-98%) and a specificity of 52% (95% CI 33-71%) to predict USCP. When asymmetrically presented FMs were also considered as abnormal, sensitivity increased to 100%, hence the specificity declined to 43%. A HAI asymmetry index cut-off of 23, had both a sensitivity and a specificity of 100% to detect USCP.

Conclusion: Using GMA and HAI can enable prediction of USCP before the age of 5 months in infants with perinatal stroke. Nevertheless, GMA must be interpreted with caution in this particular population. The HAI was found to be a very accurate screening tool for early detection of asymmetry and prediction of USCP.
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http://dx.doi.org/10.1016/j.ejpn.2020.09.002DOI Listing
November 2020

Neurodevelopmental outcomes of very preterm and very-low-birthweight infants in a population-based clinical cohort with a definite perinatal treatment policy.

Eur J Paediatr Neurol 2020 Sep 16;28:133-141. Epub 2020 Jul 16.

Department of Rehabilitation Sciences, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium. Electronic address:

Background: With constant changes in neonatal care practices, recent information is valuable for healthcare providers and for parental counselling. The aim of the study was to describe the neurodevelopmental outcome in a cohort of very preterm (VPT)/very-low-birthweight (VLBW) infants at 2 years corrected age (CA).

Material And Methods: This is a population-based cohort study of all infants born with a GA <31 weeks and/or BW < 1500 g between 2014 and 2016 admitted to the Flemish (Belgium) neonatal intensive care units. Infants had routine clinical follow-up around 2 years CA. The diagnosis of cerebral palsy (CP), visual and hearing impairments were recorded. Motor, cognitive and language outcomes were assessed using the Bayley-III. Neurodevelopmental impairment (NDI) was classified as mild (<1 standard deviation [SD]) or moderate-severe (<2SD) based on the defined categories of motor, cognitive, hearing, and vision impairments.

Results: Of the 1941 admissions, 92% survived to discharge and follow-up data were available for 1089 infants (61.1%). Overall, 19.3%, 18.9% and 41.8% of infants had a motor, cognitive and language delay, respectively. CP was diagnosed in 4.3% of the infants. Mild and moderate-to-severe NDI was observed in 25.2% and 10.9% of the infants, respectively. The number of infants with a normal outcome increased from nearly 40% in the category of GA<26 weeks to 70% for infants in the category of 30─31 weeks GA.

Conclusion: At 2 years CA, 64% were free from NDI and 90% were free from moderate-to-severe NDI. However, a lower GA and BW are associated with higher rates of adverse neurodevelopmental outcomes at 2 years CA.
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http://dx.doi.org/10.1016/j.ejpn.2020.06.007DOI Listing
September 2020

The developing brain by trimester.

Handb Clin Neurol 2020 ;171:245-289

Department of Neonatology, University Medical Center, Utrecht, The Netherlands.

Transient anatomical entities play a role in the maturation of brain regions and early functional fetal networks. At the postmenstrual age of 7 weeks, major subdivisions of the brain are visible. At the end of the embryonic period, the cortical plate covers the neopallium. The choroid plexus develops in concert with it, and the dorsal thalamus covers about half the diencephalic third ventricle surface. In addition to the fourth ventricle neuroepithelium the rhombic lips are an active neuroepithelial production site. Early reciprocal connections between the thalamus and cortex are present. The corticospinal tract has reached the pyramidal decussation, and the arteries forming the mature circle of Willis are seen. Moreover, the superior sagittal sinus has formed, and at the rostral neuropore the massa commissuralis is growing. At the viable preterm age of around 24 weeks PMA, white matter tracts are in full development. Asymmetric progenitor division permits production of neurons, subventricular zone precursors, and glial cells. Myelin is present in the ventral spinal quadrant, cuneate fascicle, and spinal motor fibers. The neopallial mantle has been separated into transient layers (stratified transitional fields) between the neuroepithelium and the cortical plate. The subplate plays an important role in organizing the structuring of the cortical plate. Commissural tracts have shaped the corpus callosum, early primary gyri are present, and opercularization has started caudally, forming the lateral fissure. Thalamic and striatal nuclei have formed, although GABAergic neurons continue to migrate into the thalamus from the corpus gangliothalamicum. Near-term PMA cerebral sublobulation is active. Between 24 and 32 weeks, primary sulci develop. Myelin is present in the superior cerebellar peduncle, rubrospinal tract, and inferior olive. Germinal matrix disappears from the telencephalon, except for the GABAergic frontal cortical subventricular neuroepithelium.
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http://dx.doi.org/10.1016/B978-0-444-64239-4.00014-XDOI Listing
January 2020

Cranial ultrasound by neonatologists.

Pediatr Res 2020 03;87(Suppl 1):1-2

Université de Paris, NeuroDiderot, Inserm, Paris, France.

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http://dx.doi.org/10.1038/s41390-020-0779-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098880PMC
March 2020

The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy.

Pediatr Res 2020 03;87(Suppl 1):59-66

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed.

Methods: (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3-7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3-7 were related to adverse outcome in univariate and the CUS of day 3-7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II).

Results: Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5-4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7-4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89).

Conclusion: This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE.
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http://dx.doi.org/10.1038/s41390-020-0782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098882PMC
March 2020

Diagnostic and predictive value of Doppler ultrasound for evaluation of the brain circulation in preterm infants: a systematic review.

Pediatr Res 2020 03;87(Suppl 1):50-58

Department of Neonatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Introduction: Very and extremely preterm infants frequently have brain injury-related long-term neurodevelopmental problems. Altered perfusion, for example, seen in the context of a hemodynamically significant patent ductus arteriosus (PDA), has been linked to injury of the immature brain. However, a direct relation with outcome has not been reviewed systematically.

Methods: A systematic review was conducted to provide an overview of the value of different cerebral arterial blood flow parameters assessed by Doppler ultrasound, in relation to brain injury, to predict long-term neurodevelopmental outcome in preterm infants.

Results: In total, 23 studies were included. Because of heterogeneity of studies, a meta-analysis of results was not possible. All included studies on resistance index (RI) showed significantly higher values in subjects with a hemodynamically significant PDA. However, absolute differences in RI values were small. Studies using Doppler parameters to predict brain injury and long-term neurodevelopmental outcome were inconsistent.

Discussion: There is no clear evidence to support the routine determination of RI or other Doppler parameters in the cerebral arteries to predict brain injury and long-term neurodevelopmental outcome in the preterm infant. However, there is evidence that elevated RI can point to the presence of a hemodynamically significant PDA.
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http://dx.doi.org/10.1038/s41390-020-0777-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098887PMC
March 2020

Cranial ultrasound findings in preterm germinal matrix haemorrhage, sequelae and outcome.

Pediatr Res 2020 03;87(Suppl 1):13-24

IRCCS, Istituto Giannina Gaslini, DINOGMI Department University of Genoa, Via Gaslini 5, 16148, Genoa, Italy.

Germinal matrix-intraventricular haemorrhage (GMH-IVH), periventricular haemorrhagic infarction (PHI) and its complication, post-haemorrhagic ventricular dilatation (PHVD), are still common neonatal morbidities in preterm infants that are highly associated with adverse neurodevelopmental outcome. Typical cranial ultrasound (CUS) findings of GMH-IVH, PHI and PHVD, their anatomical substrates and underlying mechanisms are discussed in this paper. Furthermore, we propose a detailed descriptive classification of GMH-IVH and PHI that may improve quality of CUS reporting and prediction of outcome in infants suffering from GMH-IVH/PHI.
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http://dx.doi.org/10.1038/s41390-020-0780-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098890PMC
March 2020

Abnormal primary gyration in relation to deep brain injury in preterm infants.

Acta Paediatr 2020 01 8;109(1):204-205. Epub 2019 Nov 8.

Department of Neonatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium.

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http://dx.doi.org/10.1111/apa.14996DOI Listing
January 2020

Electroencephalography and brain magnetic resonance imaging in asphyxia comparing cooled and non-cooled infants.

Eur J Paediatr Neurol 2019 Jan 12;23(1):181-190. Epub 2018 Sep 12.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands; Department of Pediatrics, Division of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands. Electronic address:

Objective: The aim was to establish any differences in the predictive value of EEG and MRI for outcome in infants treated and not-treated with therapeutic hypothermia (HT) for perinatal asphyxia. We hypothesize that they are equally predictive and that combining both has the highest predictive value.

Study Design: We retrospectively compared data of infants with hypoxic-ischemic encephalopathy (HIE) who received HT (n = 45) between September 2009 and December 2013 with those of infants with HIE born between January 2004 and August 2009, before HT was available (NT, n = 37). All received conventional and/or amplitude-integrated EEG during the first days and early MRI (day 4-5). Associations of EEG, MRI and severe neurodevelopmental outcome (death or Bayley's -2SD below mean), were tested with a multivariable logistic regression analysis, corrected for HT.

Results: Forty-eight hours' EEG background pattern had a PPV of 92% and a NPV of 81% in HT, versus 100% and 58% in NT. MRI had a PPV of 71% and a NPV of 93% in HT, versus 82% and 75% in NT. The adjusted OR for adverse outcome was 0.013 (95% CI 0.002-0.154, p < 0.001) for EEG background normalization within 48 h and 32.19 (95% CI 4.84-214.25, p < 0.001) for abnormal MRI.

Conclusion: The predictive value of EEG and MRI is equal in cooled and non-cooled infants with HIE. Our data show a higher predictive value (death and severe outcome) for EEG compared to MRI. In HIE, persistent abnormal EEG background pattern until 48 h, combined with abnormal early MRI is strongly predictive for poor neurodevelopment.
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http://dx.doi.org/10.1016/j.ejpn.2018.09.001DOI Listing
January 2019

Automated EEG background analysis to identify neonates with hypoxic-ischemic encephalopathy treated with hypothermia at risk for adverse outcome: A pilot study.

Pediatr Neonatol 2019 02 4;60(1):50-58. Epub 2018 Apr 4.

Department of Development and Regeneration, University Hospitals Leuven, Neonatal Intensive Care Unit, KU Leuven (University of Leuven), Leuven, Belgium; Department of Development and Regeneration, University Hospitals Leuven, Child Neurology, KU Leuven (University of Leuven), Leuven, Belgium.

Background: To improve the objective assessment of continuous video-EEG (cEEG) monitoring of neonatal brain function, the aim was to relate automated derived amplitude and duration parameters of the suppressed periods in the EEG background (dynamic Interburst Interval= dIBIs) after neonatal hypoxic-ischemic encephalopathy (HIE) to favourable or adverse neurodevelopmental outcome.

Methods: Nineteen neonates (gestational age 36-41 weeks) with HIE underwent therapeutic hypothermia and had cEEG-monitoring. EEGs were retrospectively analyzed with a previously developed algorithm to detect the dynamic Interburst Intervals. Median duration and amplitude of the dIBIs were calculated at 1 h-intervals. Sensitivity and specificity of automated EEG background grading for favorable and adverse outcomes were assessed at 6 h-intervals.

Results: Dynamic IBI values reached the best prognostic value between 18 and 24 h (AUC of 0.93). EEGs with dIBI amplitude ≥15 μV and duration <10 s had a specificity of 100% at 6-12 h for favorable outcome but decreased subsequently to 67% at 25-42 h. Suppressed EEGs with dIBI amplitude <15 μV and duration >10 s were specific for adverse outcome (89-100%) at 18-24 h (n = 10). Extremely low voltage and invariant EEG patterns were indicative of adverse outcome at all time points.

Conclusions: Automated analysis of the suppressed periods in EEG of neonates with HIE undergoing TH provides objective and early prognostic information. This objective tool can be used in a multimodal strategy for outcome assessment. Implementation of this method can facilitate clinical practice, improve risk stratification and aid therapeutic decision-making. A multicenter trial with a quantifiable outcome measure is warranted to confirm the predictive value of this method in a more heterogeneous dataset.
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http://dx.doi.org/10.1016/j.pedneo.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372079PMC
February 2019

Bedside Ultrasound-Guided Percutaneous Needle Aspiration of Intra- and Extra-Axial Intracranial Hemorrhage in Neonates.

Neuropediatrics 2018 08 24;49(4):238-245. Epub 2018 Apr 24.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Intracranial hemorrhage is an important cause of brain injury in the neonatal population and bedside percutaneous needle aspiration has emerged as an alternative due to the major risks that can be caused by standard neurosurgical decompression. We aimed to assess the effectiveness of this minimally invasive bedside technique and conducted a retrospective analysis of all newborn infants with a large extra-axial hemorrhage associated with a parenchymal hemorrhage causing a midline shift, managed at three academic centers over a 15-year period. Collected data included clinical history, laboratory results, review of all imaging studies performed, and neurodevelopmental follow-up. Eight infants (3 preterm and 5 full-term) presented on day 1 to 2 with seizures ( = 6) and apneas ( = 5), signs of increased intracranial pressure ( = 4), and coning ( = 1). Risk factors were present in six. Cranial ultrasound and computed tomography showed a midline shift in all; two infants showed status epilepticus on amplitude-integrated electroencephalography with complete resolution after the procedure. Between 7 and 34 mL could be aspirated associated with a decrease in the midline shift as seen by ultrasonography performed during the puncture. No complications were seen related to the procedure and none of the infants required further acute neurosurgical intervention. On follow-up, three had mild sequelae, including motor coordination problems ( = 1) and hemianopia ( = 2); none developed cerebral palsy or postneonatal epilepsy. Neonates, presenting with severe symptoms, can be managed successfully using ultrasound-guided needle aspiration and this minimally invasive bedside method should be kept in mind before performing neurosurgical decompression.
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http://dx.doi.org/10.1055/s-0038-1641568DOI Listing
August 2018

Pilot study of intracranial venous physiology in craniosynostosis.

J Neurosurg Pediatr 2018 06 6;21(6):626-631. Epub 2018 Apr 6.

6Departments of Neurology and Anesthesia (Pediatrics), Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.

OBJECTIVE In addition to craniocerebral disproportion, other factors, such as Chiari malformation type I, obstructive sleep apnea, and venous outflow obstruction, are considered to have a role in the occurrence of intracranial hypertension in craniosynostosis. This pilot study examined cerebral venous flow velocity to better characterize the complex intracranial venous physiology of craniosynostosis. METHODS The authors performed a prospective cohort study of craniosynostosis patients (n = 34) referred to a single national (tertiary) craniofacial unit. Controls (n = 28) consisted of children who were referred to the unit's outpatient clinic and did not have craniosynostosis. Transfontanelle ultrasound scans with venous Doppler flow velocity assessment were performed at the first outpatient clinic visit and after each surgery, if applicable. Mean venous blood flow velocities of the internal cerebral vein (ICV) and the superior sagittal sinus (SSS) were recorded and blood flow waveform was scored. RESULTS Preoperatively, SSS was decreased in craniosynostosis patients compared with controls (7.57 vs 11.31 cm/sec, p = 0.009). ICV did not differ significantly between patients and controls. Postoperatively, SSS increased significantly (7.99 vs 10.66 cm/sec, p = 0.023). Blood flow waveform analyses did not differ significantly between patients and controls. CONCLUSIONS Premature closure of cranial sutures was associated with decreased SSS but not ICV; indicating an effect on the superficial rather than deep venous drainage. Further Doppler ultrasound studies are needed to test the hypothesis that at an early stage of craniosynostosis pathology SSS, but not pulsatility, is abnormal, and that abnormality in both SSS and the superficial venous waveform reflect a more advanced stage of evolution in suture closure.
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http://dx.doi.org/10.3171/2018.1.PEDS17480DOI Listing
June 2018

Neonatal subcortical bruising.

Clin Case Rep 2018 02 15;6(2):407-415. Epub 2018 Jan 15.

Department of Neonatology Middelheim Hospital Antwerp Antwerp Belgium.

A specific type of acute brain injury can occur during birth, presenting on ultrasound examination with focal, unilateral, or asymmetrical change in the core of the superior frontal gyri. Ultrasound inspection of the superior gyri near the convexity of the frontal lobe is warranted following mechanically difficult delivery.
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http://dx.doi.org/10.1002/ccr3.1360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799613PMC
February 2018

Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial.

Arch Dis Child Fetal Neonatal Ed 2019 Jan 10;104(1):F70-F75. Epub 2018 Feb 10.

Department of Neonatology, Southmead Hospital, School of Clinical Science, University of Bristol, Bristol, UK.

Objective: To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation.

Design: Multicentre randomised controlled trial (ISRCTN43171322).

Setting: 14 neonatal intensive care units in six countries.

Patients: 126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III-IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm).

Intervention: Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur.

Composite Main Outcome Measure: VP shunt or death.

Results: 19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05).

Conclusions: There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches.
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http://dx.doi.org/10.1136/archdischild-2017-314206DOI Listing
January 2019

Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review.

Dev Med Child Neurol 2018 04 19;60(4):342-355. Epub 2018 Jan 19.

Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium.

Aim: The purpose of this systematic review was to provide an up-to-date global overview of the separate prevalences of motor and cognitive delays and cerebral palsy (CP) in very preterm (VPT) and very-low-birthweight (VLBW) infants.

Method: A comprehensive search was conducted across four databases. Cohort studies reporting the prevalence of CP and motor or cognitive outcome from 18 months corrected age until 6 years of VPT or VLBW infants born after 2006 were included. Pooled prevalences were calculated with random-effects models.

Results: Thirty studies were retained, which included a total of 10 293 infants. The pooled prevalence of cognitive and motor delays, evaluated with developmental tests, was estimated at 16.9% (95% confidence interval [CI] 10.4-26.3) and 20.6% (95% CI 13.9-29.4%) respectively. Mild delays were more frequent than moderate-to-severe delays. Pooled prevalence of CP was estimated to be 6.8% (95% CI 5.5-8.4). Decreasing gestational age and birthweight resulted in higher prevalences. Lower pooled prevalences were found with the Third Edition of the Bayley Scales of Infant Development than with the Second Edition.

Interpretation: Even though neonatal intensive care has improved over recent decades, there is still a wide range of neurodevelopmental disabilities resulting from VPT and VLBW births. However, pooled prevalences of CP have diminished over the years.

What This Paper Adds: The Bayley Scales of Infant and Toddler Development, Third Edition reported lower pooled prevalences of motor and cognitive delays than the Second Edition. The pooled prevalence of cerebral palsy in infants born extremely preterm was reduced compared with previous meta-analyses.
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http://dx.doi.org/10.1111/dmcn.13675DOI Listing
April 2018

Heterozygous FGA p.Asp473Ter (fibrinogen Nieuwegein) presenting as antepartum cerebral thrombosis.

Thromb Res 2018 03 28;163:185-189. Epub 2017 Oct 28.

Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Haematology, Laarbeeklaan 101, 1090 Brussels, Belgium.

Introduction: The propositus - a two-week-old boy - was transferred to our university hospital for investigation of increased head circumference and full fontanel. On ultrasound, thrombosis of the right internal cerebral vein and intraventricular haemorrhage was diagnosed, confirmed by MRI. Family history revealed a bleeding history in the mother. A haemostatic work-up in both mother and child was performed in order to rule out congenital coagulopathy.

Aim: We document a clinical case of congenital dysfibrinogenemia, caused by heterozygosity for the mutation FGA p.Asp473Ter, previously reported as fibrinogen Nieuwegein in homozygosity in an asymptomatic patient.

Methods: Fibrinogen activity in plasma was determined by functional Clauss assay, and immunological fibrinogen concentration by nephelometry. In vitro fibrin clot investigations and genetic analysis of the fibrinogen gene were performed. Complete haemostatic work-up was done by conventional methods.

Results And Discussion: After full laboratory work-up, dysfibrinogenemia was diagnosed, based on fibrinogen activity:antigen ratio, thrombin time, and reptilase time. Molecular analysis showed a frameshift mutation in exon 5 of FGA: c.1415_1416 insC, leading to a termination codon immediately after the insertion (CCT GAT>CCC TGA) and resulting in a truncated αC-domain. This mutation has been reported earlier as fibrinogen Nieuwegein. Further in vitro investigations revealed an abnormally tight clot structure, prolonged clot lysis time and affected polymerization, suggesting a thrombotic phenotype. Cerebral imaging revealed thrombosis, most likely developed in the antenatal period, leading to extensive intraventricular haemorrhage and posthaemorrhagic ventricular dilatation.

Conclusion: We highlight the combined thrombotic and haemorrhagic phenotype linked to heterozygous fibrinogen Nieuwegein, in contrast to the previously reported asymptomatic homozygous case.
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http://dx.doi.org/10.1016/j.thromres.2017.10.020DOI Listing
March 2018

Weighted Performance Metrics for Automatic Neonatal Seizure Detection Using Multiscored EEG Data.

IEEE J Biomed Health Inform 2018 07 11;22(4):1114-1123. Epub 2017 Sep 11.

In neonatal intensive care units, there is a need for around the clock monitoring of electroencephalogram (EEG), especially for recognizing seizures. An automated seizure detector with an acceptable performance can partly fill this need. In order to develop a detector, an extensive dataset labeled by experts is needed. However, accurately defining neonatal seizures on EEG is a challenge, especially when seizure discharges do not meet exact definitions of repetitiveness or evolution in amplitude and frequency. When several readers score seizures independently, disagreement can be high. Commonly used metrics such as good detection rate (GDR) and false alarm rate (FAR) derived from data scored by multiple raters have their limitations. Therefore, new metrics are needed to measure the performance with respect to the different labels. In this paper, instead of defining the labels by consensus or majority voting, popular metrics including GDR, FAR, positive predictive value, sensitivity, specificity, and selectivity are modified such that they can take different scores into account. To this end, 353 hours of EEG data containing seizures from 81 neonates were visually scored by a clinical neurophysiologist, and then processed by an automated seizure detector. The scored seizures were mixed with false detections of an automated seizure detector and were relabeled by three independent EEG readers. Then, all labels were used in the proposed performance metrics and the result was compared with the majority voting technique and showed higher accuracy and robustness for the proposed metrics. Results were confirmed using a bootstrapping test.
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http://dx.doi.org/10.1109/JBHI.2017.2750769DOI Listing
July 2018

Interrater agreement in visual scoring of neonatal seizures based on majority voting on a web-based system: The Neoguard EEG database.

Clin Neurophysiol 2017 09 12;128(9):1737-1745. Epub 2017 Jul 12.

Department of Development and Regeneration, University Hospitals Leuven, Neonatal Intensive Care Unit, KU Leuven (University of Leuven), Leuven, Belgium.

Objective: To assess interrater agreement based on majority voting in visual scoring of neonatal seizures.

Methods: An online platform was designed based on a multicentre seizure EEG-database. Consensus decision based on 'majority voting' and interrater agreement was estimated using Fleiss' Kappa. The influences of different factors on agreement were determined.

Results: 1919 Events extracted from 280h EEG of 71 neonates were reviewed by 4 raters. Majority voting was applied to assign a seizure/non-seizure classification. 44% of events were classified with high, 36% with moderate, and 20% with poor agreement, resulting in a Kappa value of 0.39. 68% of events were labelled as seizures, and in 46%, all raters were convinced about electrographic seizures. The most common seizure duration was <30s. Raters agreed best for seizures lasting 60-120s. There was a significant difference in electrographic characteristics of seizures versus dubious events, with seizures having longer duration, higher power and amplitude.

Conclusions: There is a wide variability in identifying rhythmic ictal and non-ictal EEG events, and only the most robust ictal patterns are consistently agreed upon. Database composition and electrographic characteristics are important factors that influence interrater agreement.

Significance: The use of well-described databases and input of different experts will improve neonatal EEG interpretation and help to develop uniform seizure definitions, useful for evidence-based studies of seizure recognition and management.
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http://dx.doi.org/10.1016/j.clinph.2017.06.250DOI Listing
September 2017

Effect of Preterm Birth on Echogenicity in Basal Ganglia.

Ultrasound Med Biol 2017 10 24;43(10):2192-2199. Epub 2017 Jul 24.

Department of Pediatrics, Division of Neonatology Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Neonatology, UMCU Wilhelmina Children's Hospital, Utrecht, The Netherlands. Electronic address:

In this study, the influence of prematurity on echogenicity of deep gray matter at 30-wk corrected age was assessed using ultrasound measurements. In an observational cohort study, ultrasound scans of 224 extremely preterm infants were prospectively collected. Gray values were assessed in putamen and globus pallidus. Intra- and inter-observer reliability was analyzed and showed excellent agreement. The globus pallidus to putamen ratio was significantly related to gestational age at birth, adjusted regression coefficient in points per wk: 1.28 (95% confidence interval [CI]: 0.38-2.19) for left and 2.12 (95% CI: 1.23-3.02) for right-side images. At 30-wk corrected age this was still the case, adjusted regression coefficient: 0.45 (95% CI: -0.57 to 1.47) for left and 1.29 (95% CI: 0.10-2.48) for right. The putamen is more hyperechoic with lower gestational age. Measuring ultrasound gray values in deep gray matter seems highly reproducible. Prematurity shows a negative correlation with echogenicity of the putamen, this persists at 30-wk corrected age, suggesting altered maturation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.06.017DOI Listing
October 2017

Crystal clear cerebral ultrasound images mimicking acute asphyxia in an infant with primary hyperoxaluria.

Eur J Paediatr Neurol 2017 Sep 15;21(5):792-794. Epub 2017 Jun 15.

Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Neonatology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Electronic address:

Genetic deficiencies in enzymes involved in glyoxylate metabolism lead to primary hyperoxaluria (PH) type I, typically characterized by deposition of oxalate crystals in kidneys. A 2-month-old infant was admitted, and was diagnosed with renal failure. Abdominal ultrasound images revealed enlarged and hyperechoic kidneys. Additionally, on cerebral ultrasound (CUS) hyperechoic changes of thalami and basal ganglia were noted, reminiscent of perinatal hypoxic-ischemic brain damage. However, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, in particular putamen, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts. Moreover, macular crystals were detected at ophthalmoscopy. Our case report shows the potential of US imaging to detect deposition of crystals not only in kidneys but also in brain mimicking, perinatal asphyxia.
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http://dx.doi.org/10.1016/j.ejpn.2017.06.003DOI Listing
September 2017

Differences in subependymal vein anatomy may predispose preterm infants to GMH-IVH.

Arch Dis Child Fetal Neonatal Ed 2018 Jan 6;103(1):F59-F65. Epub 2017 Jun 6.

Neonatal Intensive Care Unit, Istituto Giannina Gaslini, Genoa, Italy.

Background And Purpose: The anatomy of the deep venous system plays an important role in the pathogenesis of brain lesions in the preterm brain as shown by different histological studies. The aims of this study were to compare the subependymal vein anatomy of preterm neonates with germinal matrix haemorrhage-intraventricular haemorrhage (GMH-IVH), as evaluated by susceptibility-weighted imaging (SWI) venography, with a group of age-matched controls with normal brain MRI, and to explore the relationship between the anatomical features of subependymal veins and clinical risk factors for GMH-IVH.

Methods: SWI venographies of 48 neonates with GMH-IVH and 130 neonates with normal brain MRI were retrospectively evaluated. Subependymal vein anatomy was classified into six different patterns: type 1 represented the classic pattern and types 2-6 were considered anatomic variants. A quantitative analysis of the venous curvature index was performed. Variables were analysed by using Mann-Whitney U and χ tests, and a multiple logistic regression analysis was performed to evaluate the association between anatomical features, clinical factors and GMH-IVH.

Results: A significant difference was noticed among the six anatomical patterns according to the presence of GMH-IVH (χ=14.242, p=0.014). Anatomic variants were observed with higher frequency in neonates with GMH-IVH than in controls (62.2% and 49.6%, respectively). Neonates with GMH-IVH presented a narrower curvature of the terminal portion of subependymal veins (p<0.05). These anatomical features were significantly associated with GMH-IVH (p<0.05).

Conclusion: Preterm neonates with GMH-IVH show higher variability of subependymal veins anatomy confirming a potential role as predisposing factor for GMH-IVH.
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http://dx.doi.org/10.1136/archdischild-2017-312710DOI Listing
January 2018

Resistive indices of cerebral arteries in very preterm infants: values throughout stay in the neonatal intensive care unit and impact of patent ductus arteriosus.

Pediatr Radiol 2016 Aug 3;46(9):1291-300. Epub 2016 Jun 3.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.

Background: Little is known about cerebral artery resistive index values in infants born extremely preterm.

Objective: To report resistive index values in various cerebral arteries in a prospective cohort of preterm infants born at <29 weeks' gestation, and to compare resistive index in these arteries and assess the relationship between resistive index and hemodynamically significant patent ductus arteriosus.

Materials And Methods: Using Doppler imaging, we obtained resistive index values of internal carotid arteries, basilar artery, anterior cerebral artery, and pial and striatal arteries in the first 3 days of age and weekly thereafter until discharge or death. We analyzed paired observations using the Wilcoxon signed-rank test, between-group comparisons with the Mann-Whitney test.

Results: We performed 771 examinations in 235 infants. Resistive indices differed among arteries: vessels with larger diameters showed significantly higher resistive indices. Resistive index in infants without patent ductus arteriosus was lower than that in infants with hemodynamically significant patent ductus arteriosus (median in anterior cerebral artery: 0.75 and 0.82, respectively; P<0.001), though this was not statistically significant in all arteries. There was no difference in pre- and post-ligation resistive indices in infants who underwent patent ductus arteriosus ligation.

Conclusion: For accurate follow-up and comparison of cerebral artery resistive index, the same artery should be examined on each occasion.
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http://dx.doi.org/10.1007/s00247-016-3615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943974PMC
August 2016

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26.

Am J Hum Genet 2015 Nov 29;97(5):761-8. Epub 2015 Oct 29.

Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.

S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.
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http://dx.doi.org/10.1016/j.ajhg.2015.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667130PMC
November 2015

Improving Reliability of Monitoring Background EEG Dynamics in Asphyxiated Infants.

IEEE Trans Biomed Eng 2016 05 14;63(5):973-983. Epub 2015 Sep 14.

The goal of this study is to develop an automated algorithm to quantify background electroencephalography (EEG) dynamics in term neonates with hypoxic ischemic encephalopathy. The recorded EEG signal is adaptively segmented and the segments with low amplitudes are detected. Next, depending on the spatial distribution of the low-amplitude segments, the first part of the algorithm detects (dynamic) interburst intervals (dIBIs) and performs well on the relatively artifact-free EEG periods and well-defined burst-suppression EEG periods. However, on testing the algorithm on EEG recordings of more than 48 h per neonate, a significant number of misclassified and dubious detections were encountered. Therefore, as the next step, we applied machine learning classifiers to differentiate between definite dIBI detections and misclassified ones. The developed algorithm achieved a true positive detection rate of 98%, 97%, 88%, and 95% for four duration-related dIBI groups that we subsequently defined. We benchmarked our algorithm with an expert diagnostic interpretation of EEG periods (1 h long) and demonstrated its effectiveness in clinical practice. We show that the detection algorithm effectively discriminates challenging cases encountered within mild and moderate background abnormalities. The dIBI detection algorithm improves identification of neonates with good clinical outcome as compared to the classification based on the classical burst-suppression interburst interval.
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http://dx.doi.org/10.1109/TBME.2015.2477946DOI Listing
May 2016

Pigmented fungiform papillae of the tongue (PFPT).

Acta Clin Belg 2016 Apr 8;71(2):117-8. Epub 2016 Feb 8.

c Department of Neonatology , ZNA Middelheim , Antwerp , Belgium.

A 12-year-old African girl presented with multiple, sharply bordered hyperpigmented patches predominantly on the dorsal, tip and lateral aspects of the tongue since 1 year (Figs 1 and 2). On clinical examination, we found an obese adolescent girl with a BMI: 26.5 kg/m(2) ( > P97) with acanthosis nigricans of the neck. No medications were taken. Vitamin B12, liver tests and kidney function were normal. There was a decreased serum iron, 25OH vitamin D and zinc. Hyperinsulinism and heterozygosity for HbS (32%) were detected. Menarche: 12 years. No other family members were known with this anomaly.
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http://dx.doi.org/10.1179/2295333715Y.0000000067DOI Listing
April 2016

Neurodevelopmental outcome after neonatal perforator stroke.

Dev Med Child Neurol 2016 Jan 26;58(1):49-56. Epub 2015 Jul 26.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Aim: To assess outcome after neonatal perforator stroke in the largest cohort to date.

Method: Survivors from a cohort of children diagnosed with neonatal perforator stroke using cranial ultrasound or magnetic resonance imaging were eligible for inclusion. Recovery and Recurrence Questionnaire score, presence of cerebral palsy (CP), and crude outcome were assessed, specifically (1) the ability to walk independently, (2) participation in regular education, and (3) the presence of epilepsy.

Results: Thirty-seven patients (20 males, 17 females) aged 3 to 14 years (mean age 8y) were included in the study: 14 with isolated single perforator stroke, four with multiple isolated perforator strokes, and 19 with additional brain injury. Out of 18 children with isolated perforator stroke(s), four had CP, one could not walk independently, and one developed epilepsy. The posterior limb of the internal capsule was involved in four out of 18 patients; three of these patients had CP. Of 19 children with additional brain injury, 11 had CP and three were not able to walk independently. Three out of nine children with concomitant cortical middle cerebral artery stroke developed epilepsy.

Interpretation: Perforator stroke patterns can be of use in predicting long-term outcome and for guiding counselling and surveillance. Motor outcome was favourable in children with isolated perforator stroke(s), except when the posterior limb of the internal capsule was involved.
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http://dx.doi.org/10.1111/dmcn.12857DOI Listing
January 2016

Isolated dextrogastria in a newborn.

Arch Dis Child Fetal Neonatal Ed 2015 Nov 25;100(6):F513. Epub 2015 Jun 25.

Department of Neonatology, ZNA Middelheim Antwerp, Antwerp, Belgium.

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http://dx.doi.org/10.1136/archdischild-2014-307615DOI Listing
November 2015

Objective differentiation of neonatal EEG background grades using detrended fluctuation analysis.

Front Hum Neurosci 2015 23;9:189. Epub 2015 Apr 23.

Department of Children's Clinical Neurophysiology, HUS Medical Imaging Center and Children's Hospital, Helsinki University Central Hospital and University of Helsinki Helsinki, Finland.

A quantitative and objective assessment of background electroencephalograph (EEG) in sick neonates remains an everyday clinical challenge. We studied whether long range temporal correlations quantified by detrended fluctuation analysis (DFA) could be used in the neonatal EEG to distinguish different grades of abnormality in the background EEG activity. Long-term EEG records of 34 neonates were collected after perinatal asphyxia, and their background was scored in 1 h epochs (8 h in each neonate) as mild, moderate or severe. We applied DFA on 15 min long, non-overlapping EEG epochs (n = 1088) filtered from 3 to 8 Hz. Our formal feasibility study suggested that DFA exponent can be reliably assessed in only part of the EEG epochs, and in only relatively short time scales (10-60 s), while it becomes ambiguous if longer time scales are considered. This prompted further exploration whether paradigm used for quantifying multifractal DFA (MF-DFA) could be applied in a more efficient way, and whether metrics from MF-DFA paradigm could yield useful benchmark with existing clinical EEG gradings. Comparison of MF-DFA metrics showed a significant difference between three visually assessed background EEG grades. MF-DFA parameters were also significantly correlated to interburst intervals quantified with our previously developed automated detector. Finally, we piloted a monitoring application of MF-DFA metrics and showed their evolution during patient recovery from asphyxia. Our exploratory study showed that neonatal EEG can be quantified using multifractal metrics, which might offer a suitable parameter to quantify the grade of EEG background, or to monitor changes in brain state that take place during long-term brain monitoring.
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http://dx.doi.org/10.3389/fnhum.2015.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407610PMC
May 2015

[Kernicterus is preventable but still occurs].

Ned Tijdschr Geneeskd 2015 ;159:A8518

Radboudumc, afd. Intensive Care kinderen, Nijmegen.

Kernicterus is a severe neurological condition, caused by bilirubin-induced damage in the basal ganglia. The neurological outcome is often poor. In the past decades there seems to have been an increase in the number of reported cases of kernicterus. In order to raise awareness of this condition, we present two patients with kernicterus caused by different pathophysiological mechanisms. In both cases we make suggestions for the improvement of the medical care process. The first patient is a 7-day-old girl with kernicterus due to haemolysis caused by G6PD deficiency. Patient B is a 3-day-old boy with hyperbilirubinaemia based on 0/B blood group incompatibility. Kernicterus resulted in significant disabilities in these children. A proper diagnostic approach and precise treatment of hyperbilirubinaemia are essential to prevent major neurological damage. Awareness of this condition, education of health care professionals and changes in in- and outpatient care are needed to achieve this goal.
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December 2015

Data quality in diffusion tensor imaging studies of the preterm brain: a systematic review.

Pediatr Radiol 2015 Aug 29;45(9):1372-81. Epub 2015 Mar 29.

Division of Neonatology, Department of Pediatrics, Erasmus Medical Center - Sophia, dr. Molewaterplein 60, 3015, GJ, Rotterdam, The Netherlands,

Background: To study early neurodevelopment in preterm infants, evaluation of brain maturation and injury is increasingly performed using diffusion tensor imaging, for which the reliability of underlying data is paramount.

Objective: To review the literature to evaluate acquisition and processing methodology in diffusion tensor imaging studies of preterm infants.

Materials And Methods: We searched the Embase, Medline, Web of Science and Cochrane databases for relevant papers published between 2003 and 2013. The following keywords were included in our search: prematurity, neuroimaging, brain, and diffusion tensor imaging.

Results: We found 74 diffusion tensor imaging studies in preterm infants meeting our inclusion criteria. There was wide variation in acquisition and processing methodology, and we found incomplete reporting of these settings. Nineteen studies (26%) reported the use of neonatal hardware. Data quality assessment was not reported in 13 (18%) studies. Artefacts-correction and data-exclusion was not reported in 33 (45%) and 18 (24%) studies, respectively. Tensor estimation algorithms were reported in 56 (76%) studies but were often suboptimal.

Conclusion: Diffusion tensor imaging acquisition and processing settings are incompletely described in current literature, vary considerably, and frequently do not meet the highest standards.
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http://dx.doi.org/10.1007/s00247-015-3307-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526590PMC
August 2015