Background
Germinal matrix‐intraventricular hemorrhage (GMH‐IVH) is a common form of intracranial hemorrhage occurring in preterm neonates that may affect normal brain development. Although the ...primary lesion is easily identified on MRI by the presence of blood products, its exact extent may not be recognizable with conventional sequences. Quantitative susceptibility mapping (QSM) quantify the spatial distribution of magnetic susceptibility within biological tissues, including blood degradation products.
Purpose/Hypothesis
To evaluate magnetic susceptibility of normal‐appearing white (WM) and gray matter regions in preterm neonates with and without GMH‐IVH.
Study Type
Retrospective case‐control.
Population
A total of 127 preterm neonates studied at term equivalent age: 20 had mild GMH‐IVH (average gestational age 28.7 ± 2.1 weeks), 15 had severe GMH‐IVH (average gestational age 29.3 ± 1.8 weeks), and 92 had normal brain MRI (average gestational age 29.8 ± 1.8 weeks).
Field Strength/Sequence
QSM at 1.5 Tesla.
Assessment
QSM analysis was performed for each brain hemisphere with a region of interest‐based approach including five WM regions (centrum semiovale, frontal, parietal, temporal, and cerebellum), and a subcortical gray matter region (basal ganglia/thalami).
Statistical Tests
Changes in magnetic susceptibility were explored using a one‐way analysis of covariance, according to GMH‐IVH severity (P < 0.05).
Results
In preterm neonates with normal brain MRI, all white and subcortical gray matter regions had negative magnetic susceptibility values (diamagnetic). Neonates with severe GMH‐IVH showed higher positive magnetic susceptibility values (i.e. paramagnetic) in the centrum semiovale (0.0019 versus ‐0.0014 ppm; P < 0.001), temporal WM (0.0011 versus ‐0.0012 ppm; P = 0.037), and parietal WM (0.0005 versus ‐0.0001 ppm; P = 0.002) compared with controls. No differences in magnetic susceptibility were observed between neonates with mild GMH‐IVH and controls (P = 0.236).
Data Conclusion
Paramagnetic susceptibility changes occur in several normal‐appearing WM regions of neonates with severe GMH‐IVH, likely related to the accumulation of hemosiderin/ferritin iron secondary to diffusion of extracellular hemoglobin from the ventricle into the periventricular WM.
Level of Evidence: 4
Technical Efficacy: Stage 3
J. Magn. Reson. Imaging 2018;47:1199–1207.
The risk of oxidative stress is high in preterm newborns. Room air exposure of an organism primed to develop in a hypoxic environment, lacking antioxidant defenses, and subjected to hyperoxia, ...hypoxia, and ischemia challenges the newborn with oxidative stress production. Free radicals can be generated by a multitude of other mechanisms, such as glutamate excitotoxicity, excess free iron, inflammation, and immune reactions. Free radical-induced damage caused by oxidative stress appears to be the major candidate for the pathogenesis of most of the complications of prematurity, brain being especially at risk, with short to long-term consequences. We review the role of free radical oxidative damage to the newborn brain and propose a mechanism of oxidative injury, taking into consideration the particular maturation-dependent vulnerability of the oligodendrocyte precursors. Prompted by our observation of an increase in plasma Adenosine concentrations significantly associated with brain white matter lesions in some premature infants, we discuss a possible bioenergetics hypothesis, correlated to the oxidative challenge of the premature infant. We aim at explaining both the oxidative stress generation and the mechanism promoting the myelination disturbances. Being white matter abnormalities among the most common lesions of prematurity, the use of Adenosine as a biomarker of brain damage appears promising in order to design neuroprotective strategies.
Neonatal hypoglycemia is a common condition. A transient reduction in blood glucose values is part of a transitional metabolic adaptation following birth, which resolves within the first 48 to 72 h ...of life. In addition, several factors may interfere with glucose homeostasis, especially in case of limited metabolic stores or increased energy expenditure. Although the effect of mild transient asymptomatic hypoglycemia on brain development remains unclear, a correlation between severe and prolonged hypoglycemia and cerebral damage has been proven. A selective vulnerability of some brain regions to hypoglycemia including the second and the third superficial layers of the cerebral cortex, the dentate gyrus, the subiculum, the CA1 regions in the hippocampus, and the caudate-putamen nuclei has been observed. Several mechanisms contribute to neuronal damage during hypoglycemia. Neuronal depolarization induced by hypoglycemia leads to an elevated release of glutamate and aspartate, thus promoting excitotoxicity, and to an increased release of zinc to the extracellular space, causing the extensive activation of poly ADP-ribose polymerase-1 which promotes neuronal death. In this review we discuss the cerebral glucose homeostasis, the mechanisms of brain injury following neonatal hypoglycemia and the possible treatment strategies to reduce its occurrence.
Extra-uterine growth restriction (EUGR) is a common complication and a known risk factor for impaired development in very-low-birth-weight (VLBW) neonates. We report a population of 288 patients with ...no or with low-grade MRI lesions scanned at a term equivalent age (TEA) born between 2012 and 2018. Griffiths Mental Development Scale II (GMDS II) at 2 and 3 years, preterm complications and weight growth were retrospectively analyzed. EUGR was defined for weight z-score ˂ 10 percentile at TEA, 6 and 12 months of correct age or as z-score decreased by 1-point standard deviation (SDS) from birth to TEA and from TEA to 6 months. Multivariate analysis showed that a higher weight z-score at 6 months is protective for the global developmental quotient (DQ) at 2 years (OR 0.74; CI 95% 0.59-0.93;
= 0.01). EUGR at 6 months was associated with worse locomotor, personal/social, language and performance DQ at 2 years and worse language and practical reasoning DQ at 3 years. In conclusion, a worse weight z-score at 6 months of age seems to be an independent risk factor for significantly reduced GMDS in many areas. These results suggest that we should invest more into post-discharge nutrition, optimizing family nutritional education.
The pathogenesis of punctuate white matter lesions (PWMLs), a mild form of white matter damage observed in preterm infants, is still a matter of debate. Susceptibility-weighted imaging (SWI) allows ...to differentiate PWMLs based on the presence (SWI+) or absence (SWI-) of hemosiderin, but little is known about the significance of this distinction. This retrospective study aimed to compare neuroradiological and clinical characteristics of SWI+ and SWI- PWMLs.
MR images of all VLBW infants scanned consecutively at term-equivalent age between April 2012 and May 2018 were retrospectively reviewed, and infants with PWMLs defined as small areas of high T1 and/or low T2 signal in the periventricular white matter were selected and included in the study. Each lesion was analyzed separately and characterized by localization, organization pattern, and distance from the lateral ventricle. Clinical data were retrieved from the department database.
A total of 517 PWMLs were registered in 81 patients, with 93 lesions (18%) visible on SWI (SWI+), revealing the presence of hemosiderin deposits. On univariate analysis, compared to SWI- PWML, SWI+ lesions were closer to the ventricle wall, more frequently organized in linear pattern and associated with lower birth weight, lower gestational age, lower admission temperature, need for intubation, bronchopulmonary dysplasia, retinopathy of prematurity, and presence of GMH-IVH. On multivariate analysis, closer distance to the ventricle wall on axial scan and lower birth weight were associated with visibility of PMWLs on SWI (
= 0.003 and
= 0.0001, respectively).
Our results suggest a nosological difference between SWI+ and SWI- PWMLs. Other prospective studies are warranted to corroborate these observations.
Children born very preterm (PT) after fetal growth restriction (FGR) exhibit cognitive impairment at early school age. The relationship between neurodevelopmental impairment and attained regional ...brain volumes is unknown.
We studied 23 preterm children with FGR (PT-FGR), 24 matched preterm children AGA (PT-AGA), and 27 matched term AGA children (T-AGA) by measuring brain volumes with magnetic resonance imaging at early school age. Cognitive and motor functions were assessed by the Wechsler Intelligence Scales for Children and the ABC-Movement score.
The mean (
) full-scale IQ was 80 (17) in the PT-FGR group and 103 (12) in the PT-AGA group (
< 0.001). The PT-FGR group had lower mean total, gray matter, white matter, thalamic, cerebellar white matter, and hippocampal volumes as compared to the T-AGA group (
= 0.01, 0.04, 0.003, 0.002, 0.001, and 0.009, respectively). Brain volumes did not differ significantly between the PT groups. Reduction of hippocampal volume correlated with degree of growth restriction at birth (
= 0.46,
= 0.05). Neither the full-scale IQ nor the ABC movement score <5th percentile were related to brain volumes.
Brain volumes as determined by MRI at early school age were primarily associated with degree of prematurity at birth and less with FGR. Regional brain volumes did not discriminate cognitive and motor function beyond that predicted by gestational age at birth.
Early extubation is considered to be beneficial for pre-term neonates. On the other hand, premature extubation can cause lung derecruitment, compromised gas exchange, and need for reintubation, which ...may be associated with severe brain injury caused by sudden cerebral blood flow changes. We used near infrared spectroscopy (NIRS) to investigate changes in cerebral oxygenation (rScO
) and fractional tissue oxygen extraction (+) after extubation in pre-term infants. This is a single-center retrospective study of NIRS data at extubation time of all consecutive pre-term neonates born at our institution over a 1-year period. Comparison between subgroups was performed. Nineteen patients were included; average gestational age (GA) was 29.4 weeks. No significant change was noted in rScO
and cFTOE after extubation in the whole population. GA and germinal matrix hemorrhage (GMH)-intraventricular hemorrhage (IVH) showed a significant change in rScO
and cFTOE after extubation. A significant increase in cFTOE was noted in patients with previous GMH-IVH (+0.040;
= 0.05). To conclude, extubation
was not associated with significant change in cerebral oxygenation and perfusion. Patients with a diagnosed GMH-IVH showed an increase in cFTOE, suggesting perturbation in cerebral perfusion suggesting further understanding during this challenging phenomenon. Larger studies are required to corroborate our findings.
Placental pathology as a predisposing factor to intraventricular hemorrhage remains a matter of debate, and its contribution to cerebellar hemorrhage development is still largely unexplored. Our ...study aimed to assess placental and perinatal risk factors for intraventricular and cerebellar hemorrhages in preterm infants. This retrospective cohort study included very low-birth weight infants born at the Gaslini Children's Hospital between January 2012 and October 2016 who underwent brain magnetic resonance with susceptibility-weighted imaging at term-equivalent age and whose placenta was analyzed according to the Amsterdam Placental Workshop Group Consensus Statement. Of the 286 neonates included, 68 (23.8%) had intraventricular hemorrhage (all grades) and 48 (16.8%) had a cerebellar hemorrhage (all grades). After correction for gestational age, chorioamnionitis involving the maternal side of the placenta was found to be an independent risk factor for developing intraventricular hemorrhage, whereas there was no association between maternal and fetal inflammatory response and cerebellar hemorrhage. Among perinatal factors, we found that intraventricular hemorrhage was significantly associated with cerebellar hemorrhage (odds ratio OR, 8.14), mechanical ventilation within the first 72 h (OR, 2.67), and patent ductus arteriosus requiring treatment (OR, 2.6), whereas cesarean section emerged as a protective factor (OR, 0.26). Inotropic support within 72 h after birth (OR, 5.24) and intraventricular hemorrhage (OR, 6.38) were independent risk factors for cerebellar hemorrhage, whereas higher gestational age was a protective factor (OR, 0.76). Assessing placental pathology may help in understanding mechanisms leading to intraventricular hemorrhage, although its possible role in predicting cerebellar bleeding needs further evaluation.
Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce ...comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this
analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants.
This report is an exploratory
analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers.
The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (
= 104) showed reduced progression to GMH-IVH in treated infants (25.0% 13/52 vs. 40.4% 21/52; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed.
The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.
To evaluate punctate white matter lesion (PWML) influence in preterm infants on the long-term neurodevelopmental outcome (NDO).
PubMed and EMBASE were searched from January 1, 2000, to May 31, 2021. ...Studies were included in which PWML in preterm infants on MRI around term-equivalent age (TEA) and NDO at ≥12 months were reported. Study and patient characteristics and NDO on motor, cognitive, and behavioral domains were extracted. The quality of studies was assessed using the Cochrane-approved Quality in Prognosis Studies tool.
This analysis included nine studies with a total of 1655 patients. Mean incidence of isolated PWML was 22.1%. All studies showed a relationship between PWML and motor delay. Two studies found a significant correlation between cognitive and behavioral outcomes and PWML. Number and PWML location are related to severity and impairment types.
PWML were not always separately described from generalized WMI, only studies with imaging around TEA were included, and studies were heterogenic in design and quality.
PWML is common in preterm infants and predictive of adverse NDO, in particular on motor outcomes and less on cognitive and behavioral outcomes. The type and severity of impairments are related to the number and location of PMWL.
PWML is common in preterm infants and seems predictive of adverse NDO. DWI and SWI MRI sequences are informative because the different patterns suggest a difference in the underlying pathology. The type and severity of impairments are related to the number and location of PMWL. Our review can inform clinicians and parents about the NDO of preterm infants with a diagnosis of PWML. Prospective neuroimaging case-control cohort studies are recommended.
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