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Pediatric Research Nov 2001Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and... (Review)
Review
Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor- and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamate-mediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.
Topics: Animals; Brain; Cerebral Hemorrhage; Female; Fetal Diseases; Glutamic Acid; Humans; Infant, Newborn; Infant, Premature; Leukomalacia, Periventricular; Pregnancy; Pregnancy Complications, Infectious; Regional Blood Flow
PubMed: 11641446
DOI: 10.1203/00006450-200111000-00003 -
Neonatology 2023Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur...
INTRODUCTION
Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics.
METHODS
This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5.
RESULTS
A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age.
DISCUSSION/CONCLUSION
Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.
Topics: Infant; Female; Infant, Newborn; Humans; Leukomalacia, Periventricular; Infant, Premature; Cerebral Palsy; Prospective Studies; Infant, Premature, Diseases; Fetal Growth Retardation; Epilepsy; Seizures; Infant, Very Low Birth Weight
PubMed: 37071988
DOI: 10.1159/000529998 -
Brain Pathology (Zurich, Switzerland) Jul 2005Periventricular leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves... (Review)
Review
Periventricular leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves ischemia/reperfusion in the critically ill premature infant, with impaired regulation of cerebral blood flow, as well as inflammatory mechanisms associated with maternal and/or fetal infection. During the peak period of vulnerability for PVL, developing oligodendrocytes (OLs) predominate in the white matter. We hypothesize that free radical injury to the developing OLs underlies, in part, the pathogenesis of PVL and the hypomyelination seen in long-term survivors. In human PVL, free radical injury is supported by evidence of oxidative and nitrative stress with markers to lipid peroxidation and nitrotyrosine, respectively. Evidence in normal human cerebral white matter suggests an underlying vulnerability of the premature infant to free radical injury resulting from a developmental mismatch of antioxidant enzymes (AOE) and subsequent imbalance in oxidant metabolism. In vitro studies using rodent OLs suggest that maturational susceptibility to reactive oxygen species is dependent, not only on levels of individual AOE, but also on specific interactions between these enzymes. Rodent in vitro data further suggest 2 mechanisms of nitric oxide damage: one involving the direct effect of nitric oxide on OL mitochondrial integrity and function, and the other involving an activation of microglia and subsequent release of reactive nitrogen species. The latter mechanism, while important in rodent studies, remains to be determined in the pathogenesis of human PVL. These observations together expand our knowledge of the role that free radical injury plays in the pathogenesis of PVL, and may contribute to the eventual development of therapeutic strategies to alleviate the burden of oxidative and nitrative injury in the premature infant at risk for PVL.
Topics: Animals; Fetus; Free Radicals; Humans; Infant, Newborn; Leukomalacia, Periventricular; Models, Biological; Nitrates; Oligodendroglia; Oxidative Stress; Reperfusion Injury
PubMed: 16196389
DOI: 10.1111/j.1750-3639.2005.tb00525.x -
Expert Opinion on Investigational Drugs Mar 2022Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral...
INTRODUCTION
Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral palsy in preterm neonates. There is no proven therapy for PVL. This calls for appraisal of targeted therapies that have been investigated in animal models to evaluate their relevance in a clinical research context.
AREAS COVERED
This systematic review identifies interventions that were evaluated in preclinical studies for neuroprotective efficacy against PVL. We identified 142 studies evaluating various interventions in PVL animal models (search method is detailed in section 2).
EXPERT OPINION
Interventions that have yielded significant results in preclinical research, and that have been evaluated in a limited number of clinical trials include stem cells, erythropoietin, and melatonin. Many other therapeutic modalities evaluated in preclinical studies have been identified, but more data on their neuroprotective potential in PVL must be garnered before they can be considered for clinical trials. Because most of the tested interventions had only a partial efficacy, a combination of interventions that could be synergistic should be investigated in future preclinical studies. Furthermore, since the nature and pattern of perinatal insults to preterm brain predisposing it to PVL are substantially variable, individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates should be explored.
Topics: Animals; Brain; Female; Humans; Infant, Newborn; Leukomalacia, Periventricular; Pregnancy; Risk Factors
PubMed: 35143732
DOI: 10.1080/13543784.2022.2040479 -
Archives de Pediatrie : Organe Officiel... May 1998The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic... (Review)
Review
The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. Carrying motor and neuropsychological consequences, PVLs could be the most severe danger for very premature brains. Positive rolandic sharp waves recorded on EEG and precocious abnormally echogenous periventricular images on ultrasound suggest prospective periventricular cysts. Cystic periventricular cavitations certify the diagnosis of PVL. More subtle lesions of PVL do not reach the cystic grade and their diagnosis is confirmed by MRI. Treatment of infections is already available and potentially a tool for prevention. When the overwhelming glutamatergic signal has been triggered, neuroprotective agents turning off the excitotoxic cascade, including calcium blockers, growth factors and others, are promising therapeutic tools.
Topics: Humans; Infant, Newborn; Leukomalacia, Periventricular
PubMed: 9759189
DOI: 10.1016/s0929-693x(99)80320-0 -
European Journal of Paediatric... May 2021To describe the frequency, motor phenotype, clinical patterns and functional consequences of dystonia in patients with cerebral palsy (CP) in the setting of...
OBJECTIVE
To describe the frequency, motor phenotype, clinical patterns and functional consequences of dystonia in patients with cerebral palsy (CP) in the setting of periventricular leukomalacia.
METHODS
Retrospective analysis of a cohort of 31 patients with CP and periventricular leukomalacia. Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) were used to classify functional ability. Spasticity was rated using the Modified Ashworth Scale. Presence of dystonia was assessed by reviewing video recordings, and its severity by using the Burke-Fahn-Marsden Dystonia Rating Scale.
RESULTS
All patients showed evidence of dystonia involving upper and/or lower limbs, neck, trunk, mouth and eyes in order of frequency. In 29% of patients dystonia involved only the limbs and in 71% it was multifocal. Dystonia severity ranged from slight to severe. Severity and distribution of dystonia did not correlate with gender, age, weeks of gestation or duration of neonatal unit stay. GMFCS and MACS correlated with dystonia but not with spasticity.
CONCLUSIONS
Severity of dystonia, but not spasticity is associated with the severity of motor functional disability in CP patients with periventricular leukomalacia and demonstrates the key role of dystonia in the motor function of these patients.
Topics: Activities of Daily Living; Cerebral Palsy; Child; Child, Preschool; Cohort Studies; Dystonia; Humans; Leukomalacia, Periventricular; Male; Motor Skills; Retrospective Studies; Severity of Illness Index
PubMed: 33743389
DOI: 10.1016/j.ejpn.2021.03.005 -
The Israel Medical Association Journal... Oct 2021Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of...
BACKGROUND
Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of publications on biomarkers of cPVL.
OBJECTIVES
To determine C-reactive protein (CRP) levels during the first week of life of preterm infants who later developed cPVL and to identify the association between CRP levels with perinatal factors.
METHODS
We retrospectively included infants ≤ 32 weeks gestation and/or birth weights ≤ 1500 grams; 17 with a cranial ultrasound diagnosis of cPVL and 54 with normal ultrasounds. Serum CRP levels were measured during days 1-7 (CRP1-7d) of life and subdivided into two timing groups: days 1-3 (CRP1-3d) and days 4-7 (CRP4-7d).
RESULTS
The cPVL group had significantly higher mean CRP4-7d levels compared to controls (12.75 ± 21.2 vs. 2.23 ± 3.1, respectively, P = 0.03), while CRP1-3d levels were similar. CRP1-7d levels were significantly correlated with maximal fraction of inspired oxygen during the first 12 hours of life (FiO2-12h, r = 0.51, P < 0.001]. Additional risk factors were not associated with CRP levels.
CONCLUSIONS
Our finding of elevated CRP4-7d levels and later development of cPVL supports earlier studies on the involvement of inflammation in the pathogenesis of cPVL. Whether CRP could serve as a biomarker of cPVL and its correlation with outcomes, awaits further trials. Furthermore, the correlation between FiO2-12h and CRP1-7d levels suggest that hypoxia and/or hyperoxia may serve as a trigger in the activation of inflammation during the first days of life of preterm infants.
Topics: Biomarkers; Brain; C-Reactive Protein; Early Diagnosis; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Inflammation; Leukomalacia, Periventricular; Male; Oxygen Consumption; Risk Assessment; Risk Factors; Ultrasonography
PubMed: 34672442
DOI: No ID Found -
Journal of Child Neurology Dec 2005Periventricular leukomalacia is a form of white-matter injury that occurs in the setting of either primary or secondary hypoxia-ischemia in the premature infant.... (Review)
Review
Periventricular leukomalacia is a form of white-matter injury that occurs in the setting of either primary or secondary hypoxia-ischemia in the premature infant. Hypoxia-ischemia induces increases in cerebral extracellular glutamate levels, thereby activating glutamate receptors on a variety of cell types within the white matter. This review examines the evidence of a role for glutamate receptors in white-matter injury and periventricular leukomalacia. Multiple glutamate receptor subtypes exist, and these appear to play differential roles depending on cell type and time after injury. Glutamate receptors are developmentally regulated on neurons and glia, and certain subtypes are transiently overexpressed in developing rodent brain and are expressed on immature oligodendrocytes in human white matter in the premature period. Pharmacologic agents acting on glutamate receptors might represent age-specific therapeutic strategies for the treatment of periventricular leukomalacia.
Topics: Brain Ischemia; Humans; Hypoxia, Brain; Infant, Newborn; Infant, Premature; Leukomalacia, Periventricular; Receptors, Glutamate
PubMed: 16417841
DOI: 10.1177/08830738050200120401 -
Pediatrics and Neonatology Jan 2022
Topics: Aspirin; Epilepsy; Humans; Infant, Newborn; Leukomalacia, Periventricular; Protein S Deficiency; Seizures
PubMed: 34836816
DOI: 10.1016/j.pedneo.2021.08.017 -
Brain & Development Aug 2014To clarify the differences between infants with periventricular hemorrhagic infarction (PVHI) and those with periventricular leukomalacia (PVL).
PURPOSE
To clarify the differences between infants with periventricular hemorrhagic infarction (PVHI) and those with periventricular leukomalacia (PVL).
METHODS
We retrospectively evaluated the clinical features, ultrasonography, and electroencephalogram (EEG) findings in 22 preterm infants with PVHI and 49 with PVL. EEG and cranial ultrasonography were serially performed in all participants starting immediately after birth. Acute and chronic stage EEG abnormalities were evaluated separately.
RESULTS
Gestational age and birth weight were significantly lower in infants with PVHI than those with PVL. EEGs were normal in the majority of infants with PVHI on days 1-2. However, EEG abnormalities appeared after ultrasonography abnormalities. The majority of infants with PVL showed acute-stage EEG abnormalities on days 1-2. The rate of infants with acute-stage EEG abnormalities decreased with age, whereas the rate of infants with chronic-stage EEG abnormalities increased with age. Normal EEG before ultrasonography abnormalities was more common in infants with PVHI than in those with PVL. However, deterioration of acute-stage EEG abnormalities was more frequent in infants with PVHI than in those with PVL.
CONCLUSIONS
PVHI was presumed to cause mostly postnatal injury, whereas PVL was presumed to cause mostly pre-or perinatal injury.
Topics: Brain; Brain Infarction; Cerebral Ventricles; Electroencephalography; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intracranial Hemorrhages; Leukomalacia, Periventricular; Ultrasonography
PubMed: 23978489
DOI: 10.1016/j.braindev.2013.07.014