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Frontiers in Neurology 2016Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from... (Review)
Review
Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice-Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury.
PubMed: 27199883
DOI: 10.3389/fneur.2016.00057 -
Frontiers in Pediatrics 2022We investigated the association between cerebral tissue oxygen saturation (cStO) measured by near-infrared spectroscopy (NIRS) and cerebral lesions including...
BACKGROUND
We investigated the association between cerebral tissue oxygen saturation (cStO) measured by near-infrared spectroscopy (NIRS) and cerebral lesions including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL).
METHODS
Preterm infants <1,500 g received continuous cStO monitoring, initiated at the earliest time possible and recorded until 72 h of life. Mean cStO over periods of 5, 15, 30 min and 1 h were calculated. To calculate the burden of cerebral hypoxia, we defined a moving threshold based on the 10th percentile of cStO of healthy study participants and calculated the area under the threshold (AUT). cStO <60% for >5 min was regarded a critical event. The study was registered on clinicaltrials.gov (ID NCT01430728, URL: https://clinicaltrials.gov/ct2/show/NCT01430728?id=NCT01430728&draw=2&rank=1).
RESULTS
Of 162 infants (gestational age: mean 27.2 weeks, standard deviation 20 days; birth weight: mean 852 g, standard deviation 312 g) recorded, 24/12 (14.8%/7.4) developed any/severe IVH/PVL. Mean cStO was significantly lower in infants with IVH/PVL as well as severe IVH/PVL. In addition, we observed critical events defined by mean cStO over 5 min <60% in four infants with severe IVH/PVL during NIRS monitoring. AUT showed no statistically significant difference between outcome groups.
CONCLUSION
These findings suggest that cStO is lower in infants developing IVH/PVL. This may be related to lower oxygenation and/or perfusion and implies that cStO could potentially serve as an indicator of imminent cerebral lesions.
PubMed: 35498781
DOI: 10.3389/fped.2022.809248 -
Experimental Neurology Aug 2011Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by...
Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by hypoxia-ischemia and inflammation. Activated microglia trigger white matter damage and play a major role in the development of PVL. Erythropoietin (EPO) and its derivative carbamylated erythropoietin (CEPO) have been shown to be neuroprotective in several brain disease models. Here we investigated whether EPO and CEPO could provide protection in mouse models of PVL induced by hypoxia-ischemia or hypoxia-ischemia-inflammation. We administered EPO or CEPO to mice with PVL, and found that both EPO and CEPO treatments decreased microglia activation, oligodendrocyte damage and myelin depletion. We also noted improved performance in neurological function assays. Inhibited disease progression in PVL mice by EPO or CEPO treatment was associated with decreased poly-(ADP-ribose) polymerase-1 (PARP-1) activity. PARP-1 activity was increased dramatically in activated microglia in untreated mice with PVL. Furthermore, we demonstrated that the neuroprotective properties of EPO and CEPO were diminished after PARP-1 gene depletion. The therapeutic doses of EPO and CEPO used in this study did not interfere with normal oligodendrocyte maturation and myelination. Together, our data demonstrate that EPO and CEPO are neuroprotective in cerebral white matter injury via a novel microglial PARP-1 dependent mechanism, and hold promise as a future treatment for PVL and other hypoxic-ischemic/inflammatory white matter diseases.
Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Erythropoietin; Humans; Hypoxia; Infant, Newborn; Inflammation; Leukomalacia, Periventricular; Mice; Microglia; Myelin Sheath; Neurons; Neuroprotective Agents; Oligodendroglia
PubMed: 21596035
DOI: 10.1016/j.expneurol.2011.04.021 -
Brain & Development 1995The immature human brain undergoes remarkable organizational changes during intrauterine and postnatal life. These changes create potential temporal 'windows' of... (Review)
Review
The immature human brain undergoes remarkable organizational changes during intrauterine and postnatal life. These changes create potential temporal 'windows' of selective vulnerability to damage. For example, the temporary germinal matrix is vulnerable to hemorrhage in the third trimester fetus and premature infant. The immature oligodendroglia present in developing white matter of the fetus are also vulnerable to injury producing periventricular leukomalacia. Similar changes take place in the synapses that make up the infant's neuronal circuitry. In human cerebral cortex, synapses are produced in greater than adult numbers by postnatal age 2 years and then reduced over the next decade. Over the same period receptors for glutamate, the most important excitatory neurotransmitter, change their characteristics to allow them to participate in activity dependent synaptic plasticity. For example, the immature N-methyl-D-aspartate (NMDA) type glutamate receptor/channel complex, which plays important roles in long term potentiation (LTP), neuronal migration and synaptic pruning, contains subunits that allow the channel to be opened more easily for a longer period than adult channels. These developmental changes make the immature brain selectively vulnerable to NMDA receptor overstimulation that can occur during hypoxia-ischemia and other insults. Several types of neuropathology in the developing brain can be understood on the basis of these organizational principles.
Topics: Animals; Brain; Brain Chemistry; Excitatory Amino Acids; Humans; Neurotransmitter Agents
PubMed: 8579213
DOI: 10.1016/0387-7604(95)00079-q -
Archives of Disease in Childhood. Fetal... Mar 2008Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is... (Review)
Review
Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment. The unique cerebrovascular anatomy and physiology of the premature baby underlies the exquisite sensitivity of white matter to the abnormal milieu of preterm extrauterine life, in particular ischaemia and inflammation. These two upstream mechanisms can coexist and amplify their effects, leading to activation of two principal downstream mechanisms: excitotoxicity and free radical attack. Upstream mechanisms trigger generation of reactive oxygen and nitrogen species. The pre-OL is intrinsically vulnerable to free radical attack due to immaturity of antioxidant enzyme systems and iron accumulation. Ischaemia and inflammation trigger glutamate receptor-mediated injury leading to maturation-dependent cell death and loss of cellular processes. This review looks at recent evidence for pathogenetic mechanisms in white matter injury with emphasis on targets for prevention and treatment of injury.
Topics: Brain; Cell Death; Cytokines; Female; Fetal Diseases; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Leukomalacia, Periventricular; Male; Oligodendroglia; Pregnancy
PubMed: 18296574
DOI: 10.1136/adc.2006.108837 -
Seminars in Pediatric Neurology Oct 2019Children born preterm with periventricular leukomalacia (PVL) demonstrate increased difficulties with tasks requiring visuomotor integration. The visuomotor integration...
Children born preterm with periventricular leukomalacia (PVL) demonstrate increased difficulties with tasks requiring visuomotor integration. The visuomotor integration network encompasses brain regions within frontal, parietal, and occipital cortices. Because of their proximity to the lateral ventricle the underlying white matter pathways are at a high risk of damage following PVL-related hypoxic-ischemic white matter injury. This study provides an exploratory analysis of the structural and functional connections within the visuomotor integration network, along with an a priori evaluation of the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and frontal aslant tract. For each pathway, tracts within both hemispheres revealed decreased volume and number of reconstructed fibers and an increase in quantitative anisotropy and generalized fractional anisotropy. The connectivity results also indicate that there may be changes to both the structural integrity and functional integration of neural networks involved with visuomotor integration functions in children with PVL.
Topics: Adolescent; Anisotropy; Brain Injuries; Brain Mapping; Female; Humans; Leukomalacia, Periventricular; Male; Nerve Net; Neural Pathways; White Matter; Young Adult
PubMed: 31548024
DOI: 10.1016/j.spen.2019.05.009 -
Seminars in Fetal & Neonatal Medicine Aug 2020In 1962 a long-recognized pathologic abnormality in neonatal brains characterized by multiple telencephalic focal white matter necroses was renamed periventricular... (Review)
Review
In 1962 a long-recognized pathologic abnormality in neonatal brains characterized by multiple telencephalic focal white matter necroses was renamed periventricular leukomalacia (PVL) and the authors inappropriately asserted that their entity was caused by anoxia. They also failed to include three other white matter histologic abnormalities. In this essay, we identify the breadth of white matter pathology, especially in very preterm newborns, and show that none of the four histologic expressions of white matter damage, including focal necrosis, are associated with hypoxemia or correlates as hypotension, but are instead associated with markers of fetal or perinatal inflammation, particularly in preterm babies. We begin with the background needed to evaluate the evidence.
Topics: Brain Injuries; Female; Fetus; Humans; Infant, Newborn; Leukomalacia, Periventricular; Nerve Degeneration; Pregnancy; White Matter
PubMed: 32299712
DOI: 10.1016/j.siny.2020.101111 -
Frontiers in Neurology 2014Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between... (Review)
Review
Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matter of the developing brain. Nearly 90% of preterm infants who later develop spastic CP have evidence of periventricular white matter injury. There are currently no treatments targeted at protecting the immature preterm brain. Umbilical cord blood (UCB) contains a diverse mix of stem and progenitor cells, and is a particularly promising source of cells for clinical applications, due to ethical and practical advantages over other potential therapeutic cell types. Recent studies have documented the potential benefits of UCB cells in reducing brain injury, particularly in rodent models of term neonatal hypoxia-ischemia. These studies indicate that UCB cells act via anti-inflammatory and immuno-modulatory effects, and release neurotrophic growth factors to support the damaged and surrounding brain tissue. The etiology of brain injury in preterm-born infants is less well understood than in term infants, but likely results from episodes of hypoperfusion, hypoxia-ischemia, and/or inflammation over a developmental period of white matter vulnerability. This review will explore current knowledge about the neuroprotective actions of UCB cells and their potential to ameliorate preterm brain injury through neonatal cell administration. We will also discuss the characteristics of UCB-derived from preterm and term infants for use in clinical applications.
PubMed: 25346720
DOI: 10.3389/fneur.2014.00200 -
Artificial Intelligence in Medicine Jul 2009Periventricular leukomalacia (PVL) is part of a spectrum of cerebral white matter injury which is associated with adverse neurodevelopmental outcome in preterm infants....
OBJECTIVE
Periventricular leukomalacia (PVL) is part of a spectrum of cerebral white matter injury which is associated with adverse neurodevelopmental outcome in preterm infants. While PVL is common in neonates with cardiac disease, both before and after surgery, it is less common in older infants with cardiac disease. Pre-, intra-, and postoperative risk factors for the occurrence of PVL are poorly understood. The main objective of the present work is to identify potential hemodynamic risk factors for PVL occurrence in neonates with complex heart disease using logistic regression analysis and decision tree algorithms.
METHODS
The postoperative hemodynamic and arterial blood gas data (monitoring variables) collected in the cardiac intensive care unit of Children's Hospital of Philadelphia were used for predicting the occurrence of PVL. Three categories of datasets for 103 infants and neonates were used-(1) original data without any preprocessing, (2) partial data keeping the admission, the maximum and the minimum values of the monitoring variables, and (3) extracted dataset of statistical features. The datasets were used as inputs for forward stepwise logistic regression to select the most significant variables as predictors. The selected features were then used as inputs to the decision tree induction algorithm for generating easily interpretable rules for prediction of PVL.
RESULTS
Three sets of data were analyzed in SPSS for identifying statistically significant predictors (p<0.05) of PVL through stepwise logistic regression and their correlations. The classification success of the Case 3 dataset of extracted statistical features was best with sensitivity (SN), specificity (SP) and accuracy (AC) of 87, 88 and 87%, respectively. The identified features, when used with decision tree algorithms, gave SN, SP and AC of 90, 97 and 94% in training and 73, 58 and 65% in test. The identified variables in Case 3 dataset mainly included blood pressure, both systolic and diastolic, partial pressures pO(2) and pCO(2), and their statistical features like average, variance, skewness (a measure of asymmetry) and kurtosis (a measure of abrupt changes). Rules for prediction of PVL were generated automatically through the decision tree algorithms.
CONCLUSIONS
The proposed approach combines the advantages of statistical approach (regression analysis) and data mining techniques (decision tree) for generation of easily interpretable rules for PVL prediction. The present work extends an earlier research [Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G, Kuijpers M, Clancy RR, et al. Periventricular leukomalacia is common after cardiac surgery. J Thorac Cardiovasc Surg 2004;127:692-704] in the form of expanding the feature set, identifying additional prognostic factors (namely pCO(2)) emphasizing the temporal variations in addition to upper or lower values, and generating decision rules. The Case 3 dataset was further investigated in Part II for feature selection through computational intelligence.
Topics: Algorithms; Artificial Intelligence; Carbon Dioxide; Decision Trees; Heart Defects, Congenital; Hemodynamics; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Leukomalacia, Periventricular; Logistic Models; Postoperative Period; ROC Curve; Risk Factors
PubMed: 19162455
DOI: 10.1016/j.artmed.2008.12.005 -
Journal of Clinical Medicine Oct 2022Cystic periventricular leukomalacia (cPVL) is a major brain injury involving periventricular white matter that leads to neurodevelopmental impairment in very-low-birth...
Cystic periventricular leukomalacia (cPVL) is a major brain injury involving periventricular white matter that leads to neurodevelopmental impairment in very-low-birth weight (VLBW) infants. We investigated the neurodevelopmental outcomes (motor, cognition, visual, and hearing) of 5734 VLBW infants born between 2013 and 2019 and enrolled in the Korean Neonatal Network. Cranial ultrasound results were stratified by the presence of cPVL and severity of intraventricular hemorrhage (IVH) (no, low-grade [I/II], high-grade [III]). Neurodevelopmental impairment was evaluated using cerebral palsy for motor and Bayley Scales of Infant Development for cognition. cPVL was associated with motor, cognitive, and visual impairments in those without IVH and with low-grade IVH in pairwise comparisons (Cochran−Mantel−Haenszel p < 0.001). Conversely, cPVL was non-significantly correlated with cognitive impairment in high-grade IVH. In regression models adjusted for neonatal variables, isolated cPVL was strongly associated with motor (22.04; 11.39−42.63) and cognitive (3.10; 1.54−6.22) impairments. This study underlines the overall considerable significance of cPVL on NDI with divergent impacts depending on the severity of IVH and developmental indices.
PubMed: 36233751
DOI: 10.3390/jcm11195886