Periventricular Hemorrhagic Infarction in Very Preterm Infants: Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years.

OBJECTIVE: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013. STUDY DESIGN: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate. RESULTS: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both). CONCLUSIONS: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants.

Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years.

OBJECTIVE: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability. STUDY DESIGN: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age. RESULTS: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively). CONCLUSIONS: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Low Cerebral Oxygenation in Preterm Infants Is Associated with Adverse Neurodevelopmental Outcome.

OBJECTIVE: To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO2]) in infants born at <32 weeks of gestation were associated with adverse long-term outcome. STUDY DESIGN: Observational cohort study including preterm infants born at <32 weeks of gestation at the Wilhelmina Children's Hospital, The Netherlands, between April 2006 and April 2013. The rScO2 was continuously monitored for 72 hours after birth using near-infrared spectroscopy. Outcome was assessed at 15 and 24 months of corrected age by certified investigators. An unfavorable composite outcome was defined as an outcome score below -1 SD or death. Various rScO2 thresholds were explored. RESULTS: In total, 734 infants were eligible for analysis, 60 of whom died. Associations with an unfavorable cognitive outcome in multivariable analysis were comparable for time spent with a rScO2 below 55% and -1.5 SD (according to published reference values), with an OR of 1.4 (CI 1.1-1.7) for 20% of time below either threshold. Results at 15 months were comparable with results at 24 months. Results were not statistically significant for thresholds defining high values of rScO2. The composite motor outcome was not significantly related to either low or high values or rScO2. CONCLUSIONS: Low, but not high, rScO2 was associated with an unfavorable cognitive outcome. This suggests the use of a threshold of rScO2 <55% for future clinical studies when using adult near-infrared sensors (rScO2 <65% for neonatal sensors, approximately).

A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia.

OBJECTIVE: To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. STUDY DESIGN: This retrospective cohort study (cohort 1, The Netherlands 2008-2014; cohort 2, Sweden 2007-2012) including infants born at >36 weeks of gestational age treated with therapeutic hypothermia who had an MRI in the first weeks of life. The MRI score consisted of 3 subscores: deep grey matter, white matter/cortex, and cerebellum. Primary adverse outcome was defined as death, cerebral palsy, Bayley Scales of Infant and Toddler Development, third edition, motor or cognitive composite scores at 2 years of <85, or IQ at school age of <85. RESULTS: In cohort 1 (n = 97) and cohort 2 (n = 76) the grey matter subscore was an independent predictor of adverse outcome at 2 years (cohort 1, OR, 1.6; 95% CI, 1.3-1.9; cohort 2, OR, 1.4; 95% CI, 1.2-1.6), and school age (cohort 1, OR, 1.3; 95% CI, 1.2-1.5; cohort 2, OR, 1.3; 95% CI, 1.1-1.6). The white matter and cerebellum subscore did not add to the predictive value. The positive predictive value, negative predictive value, and area under the curve for the grey matter subscore were all >0.83 in both cohorts, whereas the specificity was >0.91 with variable sensitivity. CONCLUSION: A novel MRI score, which includes diffusion-weighted imaging and assesses all brain areas of importance in infants with therapeutic hypothermia after perinatal asphyxia, has predictive value for outcome at 2 years of age and at school age, for which the grey matter subscore can be used independently.

Concurrent Validity Between Live and Home Video Observations Using the Alberta Infant Motor Scale.

PURPOSE: Serial assessment of gross motor development of infants at risk is an established procedure in neonatal follow-up clinics. Assessments based on home video recordings could be a relevant addition. METHODS: In 48 infants (1.5-19 months), the concurrent validity of 2 applications was examined using the Alberta Infant Motor Scale: (1) a home video made by parents and (2) simultaneous observation on-site by a pediatric physical therapist. Parents' experiences were explored using a questionnaire. RESULTS: The intraclass correlation coefficient agreement between live and home video assessment was 0.99, with a standard error of measurement of 1.41 items. Intra- and interrater reliability: intraclass correlation coefficients were more than 0.99. According to 94% of the parents, recording their infant's movement repertoire was easy to perform. CONCLUSION: Assessing the Alberta Infant Motor Scale based on home video recordings is comparable to assessment by live observation. The video method is a promising application that can be used with low burden for parents and infants.

Relation between clinical risk factors, early cortical changes, and neurodevelopmental outcome in preterm infants.

Cortical folding mainly takes place in the third trimester of pregnancy and may therefore be influenced by preterm birth. The aim of this study was to evaluate the development of specific cortical structures between early age (around 30weeks postmenstrual age) and term-equivalent age (TEA, around 40weeks postmenstrual age) in 71 extremely preterm infants, and to associate this to clinical characteristics and neurodevelopmental outcome at two years of age. First, analysis showed that the central sulcus (CS), lateral fissure (LF) and insula (INS) were present at early MRI in all infants, whereas the other sulci (post-central sulcus [PCS], superior temporal sulcus [STS], superior [SFS] and inferior [IFS] frontal sulcus) were only seen in part of the infants. Relative growth from early to TEA examination was largest in the SFS. A rightward asymmetry of the surface area was seen in development between both examinations except for the LF, which showed a leftward asymmetry at both time points. Second, lower birth weight z-score, multiple pregnancy and prolonged mechanical ventilation showed negative effects on cortical folding of the CS, LF, INS, STS and PCS, mainly on the first examination, suggesting that sulci developing the earliest were the most affected by clinical factors. Finally, in this cohort, a clear association between cortical folding and neurodevelopmental outcome at two years corrected age was found, particularly for receptive language.

Brain Volumes at Term-Equivalent Age in Preterm Infants: Imaging Biomarkers for Neurodevelopmental Outcome through Early School Age.

OBJECTIVE: To evaluate the relationship between brain volumes at term and neurodevelopmental outcome through early school age in preterm infants. STUDY DESIGN: One hundred twelve preterm infants (born mean gestational age 28.6 ± 1.7 weeks) were studied prospectively with magnetic resonance imaging (imaged at mean 41.6 ± 1.0 weeks). T2- and T1-weighted images were automatically segmented, and volumes of 6 tissue types were related to neurodevelopmental outcome assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (cognitive, fine, and gross motor scores) at 24 months corrected age (n = 112), Griffiths Mental Development Scales (developmental quotient) at age 3.5 years (n = 98), Movement Assessment Battery for Children, Second Edition (n = 85), and Wechsler Preschool and Primary Scale of Intelligence, Third Edition at age 5.5 years (n = 44). Corrections were made for intracranial volume, maternal education, and severe brain lesions. RESULTS: Ventricular volumes were negatively related to neurodevelopmental outcome at age 24 months and 3.5 years, as well as processing speed at age 5.5 years. Unmyelinated white matter (UWM) volume was positively associated with motor outcome at 24 months and with processing speed at age 5.5 years. Cortical gray matter (CGM) volume demonstrated a negative association with motor performance and cognition at 24 months and with developmental quotient at age 3.5 years. Cerebellar volume was positively related to cognition at these time points. Adjustment for brain lesions attenuated the relations between cerebellar and CGM volumes and cognition. CONCLUSIONS: Brain volumes of ventricles, UWM, CGM, and cerebellum may serve as biomarkers for neurodevelopmental outcome in preterm infants. The relationship between larger CGM volumes and adverse neurodevelopment may reflect disturbances in neuronal and/or axonal migration at the UWM-CGM boundary and warrants further investigation.

Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques.

BACKGROUND: Complex neonatal cardiac surgery is associated with cerebral injury. In particular, aortic arch repair, requiring either deep hypothermic circulatory arrest (DHCA) or antegrade cerebral perfusion (ACP), entails a high risk of perioperative injury. It is unknown whether ACP results in less cerebral injury than DHCA. METHODS AND RESULTS: Thirty-seven neonates with an aortic arch obstruction presenting for univentricular or biventricular repair were randomized to either DHCA or ACP. Preoperatively and 1 week after surgery, magnetic resonance imaging was performed in 36 patients (1 patient died during the hospital stay). The presence of new postoperative cerebral injury was scored, and results were entered into a sequential analysis, which allows for immediate data analysis. After the 36th patient, it was clear that there was no difference between DHCA and ACP in terms of new cerebral injury. Preoperatively, 50% of patients had evidence of cerebral injury. Postoperatively, 14 of 18 DHCA patients (78%) had new injury versus 13 of 18 ACP patients (72%) (P=0.66). White matter injury was the most common type of injury in both groups, but central infarctions occurred exclusively after ACP (0 vs. 6/18 [33%]; P=0.02). Early motor and cognitive outcomes at 24 months were assessed and were similar between groups (P=0.28 and P=0.25, respectively). Additional analysis revealed lower postoperative arterial Pco2 as a risk factor for new white matter injury (P=0.04). CONCLUSIONS: In this group of neonates undergoing complex cardiac surgery, we were unable to demonstrate a difference in the incidence of perioperative cerebral injury after ACP compared with DHCA. Both techniques resulted in a high incidence of new white matter injury, with central infarctions occurring exclusively after ACP. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01032876.

Corticospinal Tract Injury Precedes Thalamic Volume Reduction in Preterm Infants with Cystic Periventricular Leukomalacia.

OBJECTIVES: To measure both fractional anisotropy (FA) values in the corticospinal tracts (CSTs) and volume of the thalami in preterm infants with cystic periventricular leukomalacia (c-PVL) and to compare these measurements with control infants. STUDY DESIGN: Preterm infants with c-PVL and controls with magnetic resonance imaging data acquired between birth and term equivalent age (TEA) were retrospectively identified in 2 centers. Tractography of the CST and segmentation of the thalamus were performed, and values from infants with c-PVL and controls were compared. RESULTS: Thirty-three subjects with c-PVL and 31 preterm controls were identified. All had at least 1 scan up to TEA, and multiple scans were performed in 31 infants. A significant difference in FA values of the CST was found between cases and controls on the scans both before and at TEA. Absolute thalamic volumes were significantly reduced at TEA but not on the earlier scans. Data acquired in infancy showed lower FA values in infants with c-PVL. CONCLUSIONS: Damage to the CST can be identified on the early scan and persists, whereas the changes in thalamic volume develop in the weeks between the early and term equivalent magnetic resonance imaging. This may reflect the difference between acute and remote effects of the extensive injury to the white matter caused by c-PVL.

Neonatal DTI early after birth predicts motor outcome in preterm infants with periventricular hemorrhagic infarction.

BACKGROUND: To determine the association between early neonatal diffusion tensor imaging (DTI) and the development of unilateral spastic cerebral palsy (USCP) in preterm infants with periventricular hemorrhagic infarction (PVHI). METHODS: Preterm infants with PVHI were assessed with early (≤4 wk after birth) and term-equivalent age MRI-DTI. Involvement of corticospinal tracts was assessed by visual assessment of the posterior limb of the internal capsule (PLIC) on DTI (classified asymmetrical, equivocal, or symmetrical) and by an atlas-based approach calculating fractional anisotropy asymmetry index in the PLIC. Motor outcome was assessed at ≥15 mo corrected age. RESULTS: Seven out of 23 infants with PVHI developed USCP. Their PLIC was visually scored as asymmetrical in 6 and equivocal in 1 on the early DTI. Thirteen out of 16 infants with a symmetrical motor development had a symmetrical PLIC on early DTI, the remaining 3 were equivocal. All infants with USCP had a fractional anisotropy asymmetry index of >0.05 (optimal cut-off value) on early DTI. In infants with a symmetrical motor development (n = 16), 14 had an asymmetry index ≤0.05 while 2 had an index >0.05. CONCLUSION: DTI in preterm infants with PVHI within a few weeks after birth is associated with later motor development.

Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome.

OBJECTIVE: To compare neurodevelopmental outcome, mean arterial blood pressure (MABP), and regional cerebral oxygenation (rSco2) between preterm neonates treated for hypotension and controls. STUDY DESIGN: Preterm neonates (N = 66) with a gestational age (GA) ≤32 weeks, without a patent ductus arteriosus, treated for hypotension (dopamine ≥5 µg/kg/min) were included. Neonates were matched to controls for GA, birth weight, sex, and year of birth. The rSco2 was determined by using near-infrared spectroscopy. Monitoring of MABP, rSco2, and arterial saturation was started at admission and continued for at least 72 hours. Neurodevelopmental outcome was assessed at 18 and 24 months' corrected age by using the Griffiths Mental Development Scales or the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Infants treated for hypotension spent more time with an MABP less than GA (median 9% vs 0%, P < .001) and time with an MABP/rSco2 correlation >0.5 (27% vs 17%, P < .001). Time spent with an rSco2 <50% and neurodevelopmental outcome at 18 and 24 months' corrected age were not significantly different between infants treated for hypotension and controls. The 26 neonates with an rSco2 <50% for >10% of time had a lower neurodevelopmental outcome at 18 months (median 99 vs 104, P = .02). CONCLUSION: An MABP less than GA (in weeks) was not associated with lower rSco2 or with lower neurodevelopmental outcome scores. However, regardless of MABP, low rSco2 was associated with lower neurodevelopmental outcome scores. Perfusion/oxygenation variables could be of additional value in neonatal intensive care.

Neuroimaging and neurodevelopmental outcome of preterm infants with a periventricular haemorrhagic infarction located in the temporal or frontal lobe.

AIM: The aim of the study was to compare clinical and neuroimaging characteristics and neurodevelopmental outcome in preterm infants with a periventricular haemorrhagic infarction (PVHI) located in the temporal or frontal periventricular white matter. METHOD: The study was a retrospective hospital-based study of preterm infants with a frontal PVHI (n=21; 11 males, 10 females; mean birthweight 1527g; mean gestational age 30.3wks) or temporal PVHI (n=13; five males, eight females; mean birthweight 1205g; mean gestational age 30.2wks) admitted to the neonatal intensive care unit between 1990 and 2012. The clinical course, results of neuroimaging studies, and neurodevelopmental outcomes of preterm infants with a gestational age less than 34 weeks with a confirmed PVHI on early cranial ultrasonography and/or magnetic resonance imaging were reviewed. For assessment of neurodevelopmental outcome we used the Griffiths Mental Development Scales, the Movement Assessment Battery for Children, the Gross Motor Function Classification System, the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and ophthalmological assessment. An unfavourable neurodevelopmental outcome was defined as moderately or severely atypical neurological examination during the last visit: presence of cerebral palsy, epilepsy, a hearing or visual impairment, and/or atypical cognitive development (Griffiths Mental Development Scales developmental quotient or Wechsler Preschool and Primary Scale of Intelligence <85). RESULTS: Unfavourable outcome was observed in 12 out of 13 children with a temporal PVHI compared with six out of 21 children with a frontal PVHI (p=0.002). Only one of the included infants with a PVHI in the temporal white matter developed cerebral palsy, which was due to a parietal PVHI in the contralateral hemisphere. Cognitive impairment was noted in seven infants with a frontal PVHI and five with a temporal PVHI. There were more infants with a temporal PVHI who developed visual impairment (n=5) or behavioural problems (n=7) compared with those with a frontal PVHI (visual impairment (n=2), behavioural problems (n=3). INTERPRETATION: PVHI located in the temporal or frontal lobe is almost invariably related to a typical motor outcome, but carries a risk of cognitive, behavioural, and visual problems, especially in infants with a PVHI located in the temporal lobe.

Clinical course of asymmetric motor performance and deformational plagiocephaly in very preterm infants.

OBJECTIVES: To describe the clinical courses of positional preference and deformational plagiocephaly up to 6 months corrected age (CA) in infants born at gestational age <30 weeks or birth weight <1000 g, and to explore predictive factors for the persistence of these phenomena. STUDY DESIGN: A total of 120 infants were examined 3 times each. The presence of deformational plagiocephaly and a score of 0-6 on an asymmetry performance scale served as outcome measures at 6 months CA. Predictive factors were determined using regression analysis. RESULTS: The prevalence of a positional preference of the head was 65.8% (79 of 120) at term-equivalent age (TEA) and 36.7% (44 of 120) at 3 months CA and that of deformational plagiocephaly was 30% (36 of 120) at TEA and 50% (60 of 120) at 3 months CA. At 6 months CA, 15.8% of the infants (19 of 120) scored ≥ 2 of a possible 6 on the asymmetry performance scale and 23.3% (28 of 120) had deformational plagiocephaly. Sleeping in the supine position was predictive of an asymmetric motor performance at 6 months CA. Chronic lung disease and/or slow gross motor maturation at 3 months CA predicted the persistence of deformational plagiocephaly. CONCLUSION: Infants born very preterm may develop deformational plagiocephaly. A positional preference of the head at TEA seems to be a normal aspect of these infants' motor repertoire, with limited ability to predict persistence of an asymmetric motor performance. The decreased prevalence of deformational plagiocephaly between 3 and 6 months CA indicates an optimistic course. Infants with a history of chronic lung disease and/or slow gross motor maturation merit timely intervention.

Diffusion-weighted imaging changes in cerebral watershed distribution following neonatal encephalopathy are not invariably associated with an adverse outcome.

AIM: Patterns of injury in term-born infants with neonatal encephalopathy following hypoxia-ischaemia are seen earlier and are more conspicuous on diffusion-weighted magnetic resonance imaging (DW-MRI) than on conventional imaging. Although the prognostic value of DW-MRI in infants with basal ganglia and thalamic damage has been established, data in infants in whom there is extensive injury in a watershed distribution are limited. The aim of this study was to assess cognitive and functional motor outcome in a cohort of infants with changes in a predominantly watershed distribution injury on neonatal cerebral MRI, including DWI. METHOD: DW-MRI findings in infants with neonatal encephalopathy following hypoxia-ischaemia were evaluated retrospectively. Twenty-two infants in whom DWI changes exhibited a predominantly watershed distribution were enrolled in the study (10 males, 12 females; mean birthweight 3337 g, 2830-3900 g; mean gestational age 40.5 wks, 37.9-42.1 wks). Follow-up MRI data at the age of 3 months (n=15) and over the age of 18 months (n=7) were analysed. In survivors, neurodevelopmental outcome was assessed with the Griffiths Mental Development Scales at the age of at least 18 months. Amplitude-integrated electroencephalography was used to score background patterns and the occurrence of epileptiform activity. RESULTS: DW-MRI revealed abnormalities that were bilateral in all infants and symmetrical in 10. The posterior regions were more severely affected in five infants and the anterior regions in three. Watershed injury occurred in isolation in 10 out of 22 infants and was associated with involvement of the basal ganglia and thalami in the other 12, of whom seven died. Cystic evolution, seen on MRI at age 3 months, occurred in three of the 15 surviving infants. Neurodevelopmental assessment of the surviving infants was performed at a median age of 35 months (range 18-48 mo). Of the five survivors with basal ganglia and thalamic involvement, two developed cerebral palsy, one had a developmental quotient of less than 85, and two had a normal outcome. Of the 10 infants with isolated watershed injury, nine had an early normal motor and cognitive outcome. In all infants with a favourable outcome, background recovery was seen on amplitude integrated EEG within 48 hours after birth. CONCLUSION: Extensive DWI changes in a watershed distribution in term-born neonates are not invariably associated with adverse sequelae, even in the presence of cystic evolution. Associated lesions of the basal ganglia and thalami are a better predictor of adverse sequelae than the extent and severity of the watershed abnormalities seen on DW-MRI.

Neurologic assessment tool for screening preterm infants at term age.

The screening assessment tool of the Dubowitz neonatal neurologic assessment was adapted for preterm infants. The findings identified as "warning signs" in preterm infants were identical to those found in full-term infants, suggesting that this screening tool can also be used in preterm infants at term age.

Atypical timing and presentation of periventricular haemorrhagic infarction in preterm infants: the role of thrombophilia.

AIM: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. METHOD: This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. RESULTS: Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. INTERPRETATION: An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants.

Cerebellar volume and proton magnetic resonance spectroscopy at term, and neurodevelopment at 2 years of age in preterm infants.

AIM: To assess the relation between cerebellar volume and spectroscopy at term equivalent age, and neurodevelopment at 24 months corrected age in preterm infants. METHODS: Magnetic resonance imaging of the brain was performed around term equivalent age in 112 preterm infants (mean gestational age 28wks 3d [SD 1wk 5d]; birthweight 1129g [SD 324g]). Cerebellar volume (60 males, 52 females), and proton magnetic resonance spectroscopy ((1) H-MRS) of the cerebellum in a subgroup of 58 infants were assessed in relation to cognitive, fine motor, and gross motor scores on the Bayley Scales of Infant and Toddler Development-III. Different neonatal variables and maternal education were regarded possible confounders. RESULTS: Cerebellar volume was significantly associated with postmenstrual age at time of magnetic resonance imaging. Cerebellar volume corrected for postmenstrual age was significantly and positively associated with cognition. Cognitive scores related significantly with N-acetylaspartate/choline (NAA/Cho) ratio obtained from cerebellar (1) H-MRS in 53 infants. Correction for neonatal and maternal variables did not change these results. Cerebellar variables were not related to motor performance. INTERPRETATION: In preterm infants, both cerebellar volume and cerebellar NAA/Cho ratio at term equivalent age were positively associated with cognition; however, no relation was found with motor outcome at 2 years of age. These findings support the importance of the cerebellum in cognitive development in preterm infants.

Active head lifting from supine in early infancy: an indicator for non-optimal cognitive outcome in late infancy.

AIM: To explore whether active head lifting from supine (AHLS) in early infancy is associated with cognitive outcome in the second year of life. METHOD: The presence of AHLS was always recorded in the notes of infants admitted to our tertiary neonatal intensive care unit. Random sampling was used to pair infants with AHLS with two comparison infants without AHLS whose sex, gestational age, birth year (1993-2009), time of assessment, and developmental test (Griffiths Mental Development Scales, Mental Scale of the Bayley Scales of Infant Development-II, or cognitive subtest of the Bayley Scales of Infant and Toddler Development-III) were comparable. Brain injury identified from neonatal cranial ultrasound scans was classified as no - mild or moderate - severe. Z-scores of cognitive test outcomes were calculated for multivariable analysis. RESULTS: Eighty-seven preterm (34 males, 53 females) and 40 term (17 males, 23 females) infants with AHLS were identified. AHLS was documented at a mean (corrected) age of 7.0 (SD 1.7) and 8.1 (SD 2.2) months respectively. The cognitive assessments were performed at a mean corrected age of 15.7 (SD 1.7) and 23.9 (SD 1.6) months in preterm infants, and 19.1 (SD 2.3) months in term infants. The mean cognitive outcome of preterm and term infants with AHLS was lower than that of infants without AHLS (p=0.002 and p=0.004 respectively). This remained after excluding infants with cerebral palsy with matching comparison infants (p=0.001 in preterm and p=0.001 in term infants). The mean difference was highest (1.35SD) between term male infants and comparison infants (p=0.001). INTERPRETATION: AHLS is associated with a less favourable cognitive outcome in the second year of life in preterm as well as in term-born infants than in comparison infants.

Cerebral white matter and neurodevelopment of preterm infants after coagulase-negative staphylococcal sepsis.

OBJECTIVE: Coagulase-negative staphylococci are the most common pathogens causing late-onset sepsis in the neonatal intensive care unit. Neonatal sepsis can be associated with cerebral white matter damage in preterm infants. Neurodevelopment has been shown to be correlated with apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivities of the white matter. DESIGN: Prospective cohort study. SETTING: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. PATIENTS: Seventy preterm infants (gestational age <32 wks), 28 with coagulase-negative staphylococcal sepsis (group 1) and 42 without sepsis (group 2). INTERVENTION: The values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of three white matter regions (parietal, frontal, and occipital), estimated with diffusion-tensor magnetic resonance imaging with a 3.0-T magnetic resonance imaging system, were obtained at term-equivalent age. Neurodevelopmental outcome assessments were performed at 15 months (Griffiths Mental Developmental Scales) and 24 months (Bayley Scales of Infant and Toddler Development, Third Edition) corrected age. MEASUREMENTS AND MAIN RESULTS: Values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of the left and right white matter regions were equal in all patients. There was no significant difference in apparent diffusion coefficient values (mean of total: 1.593 ± 0.090 × 10mm(-3)/sec(2) and 1.601 ± 0.117 × 10mm(-3)/sec(2), respectively, p = .684), fractional anisotropy values (mean of total: 0.19 ± 0.04 and 0.19 ± 0.03, respectively, p = .350), radial diffusivity (mean of total: 1.420 ± 0.09 × 10mm(-3)/sec(2)and 1.425 ± 0.12 × 10mm(-3)/sec(2), respectively, p = .719), and axial diffusivity (mean of total: 1.940 ± 0.12 × 10mm(-3)/sec(2) and 1.954 ± 0.13 × 10mm(-3)/sec(2), respectively, p = .590) in the three combined regions between the two groups. No significant differences were found in neurodevelopmental outcome at 24 months. CONCLUSIONS: No association was found between coagulase-negative staphylococcal sepsis in preterm infants and cerebral white matter damage as determined by values of apparent diffusion coefficients, fractional anisotropy, and radial and axial diffusivity at term-equivalent age, and no adverse effect was seen on early neurodevelopmental outcome.

Does diffusion tensor imaging-based tractography at 3 months of age contribute to the prediction of motor outcome after perinatal arterial ischemic stroke?

BACKGROUND AND PURPOSE: After perinatal arterial ischemic stroke, diffusion-weighted imaging (DWI) and early evaluation of spontaneous motor behavior can be used to predict the development of unilateral motor deficits. The aim of this study was to investigate whether diffusion tensor imaging-based tractography at 3 months of age contributes to this prediction. METHODS: Twenty-two infants with unilateral perinatal arterial ischemic stroke were included and scanned during the neonatal period. DWI was used to assess restricted diffusion in the cerebral peduncle. At the age of 3 months, diffusion tensor imaging-based tractography of the corticospinal tracts was performed along with assessment of the movement repertoire. The role of DWI, diffusion tensor imaging, and motor assessment in predicting unilateral motor deficits were compared by calculating the positive and negative predictive values for each assessment. RESULTS: Eleven infants (50%) showed abnormal motor behavior at 3 months with subsequent development of unilateral motor deficits in 8 as determined at follow-up (9-48 months, positive predictive value 73%). Diffusion tensor imaging-based tractography correctly predicted the development of unilateral motor deficits in all 8 infants (positive predictive value 100%). A diagnostic neonatal DWI was available in 20 of 22 (91%) infants. Seven infants showed an abnormal DWI, resulting in unilateral motor deficits in 6 infants (positive predictive value 86%). All assessments had a negative predictive value of 100%. CONCLUSIONS: Diffusion tensor imaging-based tractography at 3 months can be used to predict neurodevelopmental outcome after perinatal arterial ischemic stroke. It has a similar predictive value as DWI in the neonatal period and can especially be of additional value in case of an indecisive neonatal DWI or unexpected abnormal early motor development.