BACKGROUND AND PURPOSE: Research into memory deficits associated with hypoxic-ischemic encephalopathy has typically focused on the hippocampus, but there is emerging evidence that the medial diencephalon may also be compromised. We hypothesized that mammillary body damage occurs in perinatal asphyxia, potentially resulting in mammillary body atrophy and subsequent memory impairment. MATERIALS AND METHODS: We retrospectively reviewed brain MRIs of 235 clinically confirmed full-term patients with hypoxic-ischemic encephalopathy acquired at a single center during 2004–2017. MRIs were performed within 10 days of birth (median, 6; interquartile range, 2). Two radiologists independently assessed the mammillary bodies for abnormal signal on T2-weighted and DWI sequences. Follow-up MRIs were available for 9 patients; these were examined for evidence of mammillary body and hippocampal atrophy. RESULTS: In 31 neonates (13.2%), abnormal high mammillary body signal was seen on T2-weighted sequences, 4 with mild, 25 with moderate, and 2 with severe hypoxic-ischemic encephalopathy. In addition, restricted diffusion was seen in 6 neonates who had MR imaging between days 5 and 7. For these 31 neonates, the most common MR imaging pattern (41.9%) was abnormal signal restricted to the mammillary bodies with the rest of the brain appearing normal. Follow-up MRIs were available for 9 patients: 8 acquired between 3 and 19 months and 1 acquired at 7.5 years. There was mammillary body atrophy in 8 of the 9 follow-up MRIs. CONCLUSIONS: Approximately 13% of full-term infants with hypoxic-ischemic encephalopathy showed abnormal high mammillary body signal on T2-weighted images during the acute phase, which progressed to mammillary body atrophy in all but 1 of the infants who had follow-up MR imaging. This mammillary body involvement does not appear to be related to the severity of encephalopathy, MR imaging patterns of hypoxic-ischemic encephalopathy, or pathology elsewhere in the brain.

An observational case-control study of neonates with a confirmed RASopathy was conducted. The authors reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1. The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1. Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. BACKGROUND AND PURPOSE: Neuroimaging features in neonates with RASopathies are rarely reported, and to date, there are no neuroimaging studies conducted in this population. Our aim was to investigate the occurrence of supratentorial and posterior fossa abnormalities on brain MRIs of neonates with a RASopathy. MATERIALS AND METHODS: An observational case-control study of neonates with a confirmed RASopathy was conducted. The presence of an intraventricular and/or parenchymal hemorrhage and punctate white matter lesions and assessments of the splenium of the corpus callosum, gyrification of the cortical gray matter, and enlargement of the extracerebral space were noted. The vermis height, transverse cerebellar diameter, cranial base angle, tentorial angle, and infratentorial angle were measured. RESULTS: We reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1 (P < .001, for each). The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1 (P = .01, P < .001, and P = .001, respectively). CONCLUSIONS: Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. This study provides novel neuroimaging findings on supratentorial and posterior fossa abnormalities in neonates with a RASopathy.

latent remains unclear. Materials and methods RSV persistently infected HEp-2 cells were isolated and the clones were passaged. By using siRNA silence of RIG-I or TRL3, protein levels of SOCS1, SOCS3 and STAT1/2 in the viral persistent cells were checked by western blot, cytokines concentrations in the supernatant of were determined by ELISA, and antiviral genes expression was detected by RT-PCR. Results The RSV persistent cells always differentiated into two distinct populations characterised by viral permission or resistance respectively. The viral persistent cells produced a low viral titer, resisted wild-type RSV superinfection, and secreted high levels of IFN-b, Mip-a, IL-8 and Rantes. TLR3, RIG-I and SOCS1 were found to be upregulated. The silence of TLR3 decreased the expression of SOCS1 and the secretion of cytokines. Conclusion RSV persistent cells are in an inflammatory state that the upregulation of SOCS1 is related to the TLR3 induced signalling pathway, which could be associated with viral persistence.

Background and aims Quantitative measurement of brain maturation is increasingly performed in preterm infants using diffusion tensor imaging (DTI). To study white matter properly, reliability of underlying DTI data is of paramount importance, as acquisition and processing steps can substantially affect DTI analyses. We systematically reviewed literature to raise awareness regarding these matters. Methods We systematically reviewed studies published between 1991 and September 2013, in which DTI scanning of preterm infants was performed within 28 days after term-equivalent age. Based on our inclusion criteria, 75 preterm DTI studies were considered relevant and further analysed. We primarily focused on use of dedicated neonatal equipment, DTI acquisition parameters and processing methodology. Results There was wide variation among different studies in acquisition and processing methodology, and frequently incomplete reporting of these settings. 25.3% reported the use of dedicated neonatal equipment. Data quality assessment was not reported in 34.7%. Correction for artefacts and exclusion of datasets was not reported in 45.3% respectively 30.7%. Only 54.7% of the studies reported specific correction methods. Tensor estimation methodology was reported in 82.7%. Fast but less accurate tensor calculation algorithms were applied more frequently than advanced algorithms. Conclusion DTI acquisition and processing settings are described incompletely in current literature, and vary considerably among different neonatal DTI research groups. In addition, described settings do frequently not meet the highest standards possible. Hence the premature population should be regarded as one of the most challenging groups to image using DTI, maximal awareness regarding these matters is a prerequisite.

Advances in neuroimaging techniques have greatly improved the detection and understanding of neonatal stroke. Reported incidence of neonatal stroke in term newborns ranges from 1 in 2300 to 1 in 5900. Benders et al reported an incidence of 7 in 1000 preterm admissions. In most cases of neonatal stroke, the middle cerebral artery (MCA) is involved. For each of the cerebral arteries, main branch (cortical or pial) or perforator branch involvement can be distinguished. So far, studies on neonatal stroke have mainly focused on cortical stroke. Perforator stroke is apparently still under-recognized and little is known about risk factors and clinical presentation. To gain more insight into risk factors, clinical presentation, and neuroimaging findings of neonatal perforator stroke, we report the largest cohort of neonates to date diagnosed with perforator stroke.

Background and Aims Diffusion Tensor Imaging (DTI) has become valuable for quantitative evaluation of white matter maturation in preterm infants. Because of the occurrence of head movement, gathering good quality data is challenging in neonatal neuroimaging. This is especially of concern for DTI, where motion can result in severe signal drop-out and therefore miscalculation of DTI parameters if data outliers are not handled correctly. This study was aimed to quantify the occurrence of motion artefacts in neonatal DTI and to evaluate different methods for tensor estimation. Methods We prospectively collected DTI data of 27 preterm infants that were scanned at 30 weeks gestational age. DTI data was acquired in 25 directions. Percentage outliers per slice was calculated. With Explore DTI, we assessed the effect of motion artefacts on tensor estimation using different methods. Results 60% of subjects had slightly corrupted data (>15 slices with >30% outliers) of which 40% had severely corrupted data (>10 slices with >50% outliers). Corrupted data resulted in erroneous DTI parameters. This was especially true for the tensor estimation (ordinary least squares) typically performed by vendors and popular DTI software. More advanced tensor estimations showed more reliable data. Conclusions Motion artefacts are a major problem in neonatal DTI as it can compromise accurate calculation of DTI parameters. These results press the need for careful data inclusion and the use of reliable methods for tensor estimation. Targeted acquisition, processing and quality assessment is needed in this population to obtain reliable evaluation of white matter maturation.

Background and Aims Brain injury is an important complication of neonatal Extra Corporeal Membrane Oxygenation (ECMO). Unilateral carotid artery and jugular vein cannulation (often with ligation), in combination with systemic heparinisation, increases the risk of brain injury in an already vulnerable group of patient. The reported prevalence of brain injury ranges from 10–52% of patients treated with neonatal ECMO. Monitoring of intracranial lesions during the ECMO procedure is therefore important for treatment and prediction of outcome. Our objective is to study incidence and classification of ultrasound proven brain injury during neonatal ECMO in the Netherlands. Methods Retrospective, nationwide study (Rotterdam and Nijmegen), spanning two decades. Cranial ultrasound images were reviewed by two independent investigators, without knowledge of primary diagnosis, outcome or type of ECMO. Results 676 neonates with neonatal ECMO were studied. ECMO type was V-A in 88%. Brain abnormalities were detected in 17.3% of patients: primary hemorrhage was diagnosed most frequent (8.8%). A noticeable result was found in stroke patients (5% of the total group), where there was a significant predominance of lesions in the left hemisphere. Lobar haematoma (prevalence 2.2%) was also significantly left sided predominant. Conclusion Our study shows an incidence of ECMO-associated neonatal brain injury in the Netherlands in 17.3%. Left hemisphere lesion preference suggests that shift of brain perfusion from right to left is more important than large vessel ligation in the neck. Prevention has to focus on embolism and on management of this perfusion shift.

Background and Aims: Perinatal asphyxia is an important cause of permanent brain injury in term infants. An important neuroimaging indicator of neurodevelopmental prognosis following perinatal asphyxia is the extent of thalamic involvement. However the different patterns of injury seen within thalamus remain unclear. We used diffusion tensor imaging to study these patterns. Methods: In this retrospective study, we analysed DTI scans of 24 patients diagnosed with perinatal asphyxia, scanned between day 4-7 after birth. Images were acquired using a GE 1.5 Tesla system. Regions of interest were manually placed in four different thalamic regions (ventrolateral, medial, anterior and posterior region) and four localisations in cortex (prefrontal, parietal (post S1), occipital and temporal). ADC values were calculated using ‘DTI-studio’. Pearson's correlation coefficient and a multiple regression analysis were used (SPSS 17.0) to study relations between cortical and thalamic values. Results: We found significant correlations between prefrontal cortical ADC values and (connected) anterior- and medial thalamic regions. Temporal ADC values were correlated to Posterior thalamic regions. Occipital and parietal cortex showed highest correlation with posterior thalamic regions. Conclusions: Our study reveals significant correlations between the decrease of ADC values of thalamic nuclei and their anatomically corresponding cortical areas in perinatal asphyxia. These findings help explain different injury patterns seen within the asphyxiated thalamus. Unravelling these thalamic injury patterns using DTI could provide insights needed to improve our prognostication following perinatal asphyxia.

Developmental venous anomaly (DVA) is the most frequent vascular malformation of the brain and is often diagnosed incidentally beyond childhood (1,2). DVA is characterized by a convergence of multiple venules that drain into a dilated superficial or deep vein. DVA is thought to represent a primary dysplasia of capillaries and small transcerebral veins (3) or a compensatory mechanism caused by an intrauterine accident resulting in thrombosis of normal venous pathways (4). Despite its congenital basis, neonatal diagnosis of a DVA is reported only once – a case of a huge DVA in association with polymicrogyria (5).

Introduction:Here (and in an accompanying article dealing with definitions, differential diagnosis and registration), a structured sequential diagnostic flow is proposed to discern clinical phenotypes for perinatal stroke, including arterial ischaemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) and haemorrhagic stroke.Material and results:For neonatal AIS, the diagnostic sequence is infection, trauma, embolism, arteriopathy, other, primary thrombosis and unclassifiable; for neonatal CSVT, the sequence is infection, trauma, venopathy, other, primary thrombosis and unclassifiable. The proposed hierarchical diagnostic flows are an initial step towards a standard for registration of the causes of neonatal stroke. Such standardization should guide attempts at prevention and intervention. An extensive literature search and study of a retrospective cohort of 134 newborn infants with stroke suggest that embolism is the most common identifiable cause for stroke in general (25%), preceding trauma (10%) and infection (8%). Other causes, such as asphyxia, acute blood loss, extracorporeal membrane oxygenation, genetic disorders or prothrombotic conditions, are seen in < 5% of cases. For neonatal AIS, the presence of an embolic phenotype is 33% in this cohort. The designation unclassifiable scored 34% for the entire stroke group and 25% for neonatal AIS. Complex arterial stroke with multiple arteries involved is often seen when the underlying cause is infection, cranial trauma or embolism. One important conclusion is that a means of prevention is avoidance of embolism from thrombosis outside the brain.Conclusion:To prevent the occurrence and recurrence of neonatal ischaemic stroke, clinicians must develop a standardized diagnostic approach that results in characterization of the clinical phenotype.

Summary Background Besides short stature, gonadal dysgenesis leading to a lack of oestrogen is one of the main characteristics of Turner syndrome (TS). In most TS girls, puberty is induced with exogenous oestrogens. Objective To describe the pubertal development and uterine dimensions achieved by low‐dose 17β‐oestradiol (17β‐E2) orally started at an appropriate age. Additionally, to determine whether serum hormone levels aid evaluation of pubertal progression. Design In 56 TS girls, we prospectively studied pubertal stage, serum E2, LH, FSH, SHBG and oestrone (E1), starting oestrogen treatment with a low‐dose 17β‐E2 (5 µg/kg/day) during GH treatment at mean (SD) age 12·7 (0·7) years. Hormone levels were measured at start, 3 months after start and after increasing 17β‐E2 dosage. Uterine dimensions were measured in 39 TS women at age 19·9 (2·2) years. Results Although breast and pubic hair development were similar to that in normal Dutch girls up to Tanner stage B5 and P5, respectively, breast development was 2 years later. Before oestrogen therapy, E2 levels were comparable to those in prepubertal girls. With a 17β‐E2 dose of 5 µg/kg/day, these levels increased significantly, becoming comparable to normal late pubertal or adult concentrations, whereas SHBG levels were unchanged. At the adult 17β‐E2 dose, SHBG had increased significantly. Uterus shape was juvenile in four (10·2%), cylindrical in four and mature‐adult shaped in 31 (79·5%) of TS patients. Conclusions During GH treatment in TS girls, normal breast development up to B5 can be mimicked, with just a 2‐year delay. In a clinical setting, serum hormone levels provide no additional information for evaluating pubertal progression. After age‐appropriate pubertal induction, uterine dimensions in women aged nearly 20 years were subnormal. It remains unclear whether this was related to E2 dosage, timing or duration, or factors related to TS.

Background. The aim of this study was to evaluate the value of follow-up investigations of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell non-Hodgkin's lymphoma (T-NHL), including cerebrospinal fluid (CSF) examination, bone marrow (BM) aspiration, peripheral blood (PB) count, serum lactate dehydrogenase (LDH) and chest X-rays in patients with an initial mediastinal enlargement. Procedure. We reviewed clinical records of all T-ALL patients from 1987 to 2002 and all T-NHL patients from 1977 to 2002, seen at a single institution. Results. Of 48 T-ALL patients, 15 suffered from a relapse, 6 (40%) were asymptomatic at the time of relapse. T-ALL (13/30) with mediastinal enlargement at first diagnosis relapsed versus 2/16 of those without mediastinal enlargement. However, at relapse, only one patient had a mediastinal mass, which in addition was symptomatic. Of 39 T-NHL patients, 6 patients relapsed. Forty percent of relapsed T-ALL and 17% of relapsed T-NHL were asymptomatic. The seven asymptomatic relapses were detected by CSF (n = 4), BM (n = 2) or blood count (n = 1) examinations. All TALL and T-NHL patients with a mediastinal relapse were symptomatic. Conclusions. This study suggests that routine CSF examinations during treatment can detect relapses of T-ALL and T-NHL before onset of symptoms, which might be of clinical value. Relapses are rarely detected by BM or blood examinations and whether this translates in a clinical benefit is unlikely. Routine chest X-rays are not useful. Pediatr Blood Cancer 2007;48:468-472. (c) 2006 Wiley-Liss, Inc.