Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
To evaluate the hypothesis that the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-alpha might be the link between prenatal intrauterine infection (IUI) and neonatal brain damage, the authors review the relevant epidemiologic and cytokine literature. Maternal IUI appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. IL-1, IL-6, and TNF-alpha have been found associated with IUI, preterm birth, neonatal infections. and neonatal brain damage. Unifying models not only postulate the presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood-brain barrier) between these compartments, but also postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection. Interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.
Front Pharmacol. 2012 ;3 :46 22479246
Department of Pharmacology, The University of Melbourne Parkville, VIC, Australia.
The adult brain functions within a well-controlled stable environment, the properties of which are determined by cellular exchange mechanisms superimposed on the diffusion restraint provided by tight junctions at interfaces between blood, brain and cerebrospinal fluid (CSF). These interfaces are referred to as "the" blood-brain barrier. It is widely believed that in embryos and newborns, this barrier is immature or "leaky," rendering the developing brain more vulnerable to drugs or toxins entering the fetal circulation from the mother. New evidence shows that many adult mechanisms, including functionally effective tight junctions are present in embryonic brain and some transporters are more active during development than in the adult. Additionally, some mechanisms present in embryos are not present in adults, e.g., specific transport of plasma proteins across the blood-CSF barrier and embryo-specific intercellular junctions between neuroependymal cells lining the ventricles. However developing cerebral vessels appear to be more fragile than in the adult. Together these properties may render developing brains more vulnerable to drugs, toxins, and pathological conditions, contributing to cerebral damage and later neurological disorders. In addition, after birth loss of protection by efflux transporters in placenta may also render the neonatal brain more vulnerable than in the fetus.
Neurol Res Int. 2012 ;2012 :102153 22135745
Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 432, 40530 Göteborg, Sweden.
A growing body of evidence demonstrates that susceptibility and progression of both acute and chronic central nervous system disease in the newborn is closely associated with an innate immune response that can manifest from either direct infection and/or infection-triggered damage. A common feature of many of these diseases is the systemic exposure of the neonate to bacterial infections that elicit brain inflammation. In recent years, the importance of innate immune receptors in newborn brain injury, the so-called Toll-like receptors, has been demonstrated. In this paper we will discuss how neonatal sepsis, with particular emphasis on Escherichia coli, coagulase-negative staphylococci, and group B streptococcal infections in preterm infants, and Toll-like receptor-mediated inflammation can increase the vulnerability of the newborn brain to injury.
Lab Anim Res. 2011 Jun ;27 (2):77-84 21826166
Ehn-Kyoung Choi, Dongsun Park, Tae Kyun Kim, Sun Hee Lee, Dae-Kwon Bae, Goeun Yang, Yun-Hui Yang, Jangbeen Kyung, Dajeong Kim, Woo Ryoung Lee, Jun-Gyo Suh, Eun-Suk Jeong, Seung U Kim, Yun-Bae Kim
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Periventricular leukomalacia, specifically characterized as white matter injury, in neonates is strongly associated with the damage of pre-myelinating oligodendrocytes. Clinical data suggest that hypoxia-ischemia during delivery and intrauterine or neonatal infection-inflammation are important factors in the etiology of periventricular leukomalacia including cerebral palsy, a serious case exhibiting neurobehavioral deficits of periventricular leukomalacia. In order to explore the pathophysiological mechanisms of white matter injury and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, novel animal models have been developed using hypoperfusion, microbes or bacterial products (lipopolysaccharide) and excitotoxins. Such efforts have developed rat models that produce predominantly white matter lesions by adopting combined hypoxia-ischemia technique on postnatal days 1-7, in which unilateral or bilateral carotid arteries of animals are occluded (ischemia) followed by 1-2 hour exposure to 6-8% oxygen environment (hypoxia). Furthermore, low doses of lipopolysaccharide that by themselves have no adverse-effects in 7-day-old rats, dramatically increase brain injury to hypoxic-ischemic challenge, implying that inflammation sensitizes the immature central nervous system. Therefore, among numerous models of periventricular leukomalacia, combination of hypoxia-ischemia-lipopolysaccharide might be one of the most-acceptable rodent models to induce extensive white matter injury and ensuing neurobehavioral deficits for the evaluation of candidate therapeutics.
Cerebellum. 2012 Mar ;11 (1):132-44 21773814
Increased number of cerebellar granule cells and astrocytes in the internal granule layer in sheep following prenatal intra-amniotic injection of lipopolysaccharide.
Eveline Strackx, Markus Gantert, Veronique Moers, Imke A J van Kooten, Rebecca Rieke, Hanna Hürter, Marijke A M Lemmens, Harry W M Steinbusch, L J I Zimmermann, Johannes S H Vles, Yves Garnier, Antonio W D Gavilanes, Boris W Kramer
Department of Neuroscience and European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands.
Chorioamnionitis is an important problem in perinatology today, leading to brain injury and neurological handicaps. However, there are almost no data available regarding chorioamnionitis and a specific damage of the cerebellum. Therefore, this study aimed at determining if chorioamnionitis causes cerebellar morphological alterations. Chorioamnionitis was induced in sheep by the intra-amniotic injection of lipopolysaccharide (LPS) at a gestational age (GA) of 110 days. At a GA of 140 days, we assessed the mean total and layer-specific volume and the mean total granule cell (GCs) and Purkinje cell (PC) number in the cerebelli of LPS-exposed and control animals using high-precision design-based stereology. Astrogliosis was assessed in the gray and white matter (WM) using a glial fibrillary acidic protein staining combined with gray value image analysis. The present study showed an unchanged volume of the total cerebellum as well as the molecular layer, outer and inner granular cell layers (OGL and IGL, respectively), and WM. Interestingly, compared with controls, the LPS-exposed brains showed a statistically significant increase (+20.4%) in the mean total number of GCs, whereas the number of PCs did not show any difference between the two groups. In addition, LPS-exposed animals showed signs of astrogliosis specifically affecting the IGL. Intra-amniotic injection of LPS causes morphological changes in the cerebellum of fetal sheep still detectable at full-term birth. In this study, changes were restricted to the inner granule layer. These cerebellar changes might correspond to some of the motor or non-motor deficits seen in neonates from compromised pregnancies.
Zeynep Alpay Savasan, Tinnakorn Chaiworapongsa, Roberto Romero, Youssef Hussein, Juan Pedro Kusanovic, Yi Xu, Zhong Dong, Chong Jai Kim, Sonia S Hassan
Perinatology Research Branch, NICHD/NIH/DHHS , Detroit, Michigan , United States.
Objective: The fetal inflammatory response syndrome (FIRS) is considered the fetal counterpart of the systemic inflammatory response syndrome (SIRS), which can be caused by infection and non-infection-related insults. Although the initial response is mediated by pro-inflammatory signals, the control of this response is achieved by anti-inflammatory mediators which are essential for the successful outcome of the affected individual. Interleukin (IL)-19 is capable of stimulating the production of IL-10, a major anti-inflammatory cytokine, and is a potent inducer of the T-helper 2 (Th2) response. The aim of this study was to determine if there is a change in umbilical cord plasma IL-19 and IL-10 concentrations in preterm neonates with and without acute funisitis, the histologic counterpart of FIRS. Methods: A case-control study was conducted including 80 preterm neonates born after spontaneous labor. Neonates were classified according to the presence (n = 40) or absence of funisitis (n = 40), which is the pathologic hallmark of FIRS. Neonates in each group were also matched for gestational age. Umbilical cord plasma IL-19 and IL-10 concentrations were determined by ELISA. Results: 1) The median umbilical cord plasma IL-19 concentration was 2.5-fold higher in neonates with funisitis than in those without funisitis (median 87 pg/mL; range 20.6-412.6 pg/mL vs. median 37 pg/mL; range 0-101.7 pg/mL; p < 0.001); 2) newborns with funisitis had a significantly higher median umbilical cord plasma IL-10 concentration than those without funisitis (median 4 pg/mL; range 0-33.5 pg/mL vs. median 2 pg/mL; range 0-13.8 pg/mL; p < 0.001); and 3) the results were similar when we included only patients with funisitis who met the definition of FIRS by umbilical cord plasma IL-6 concentrations ≥ 17.5 pg/mL (p < 0.001). Conclusion: IL-19 and IL-10 are parts of the immunologic response of FIRS. A subset of fetuses with FIRS had high umbilical cord plasma IL-19 concentrations. In utero exposure to high systemic concentrations of IL-19 may reprogram the immune response.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery, Stanford University, Stanford, California, USA.
Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor-α (TNF-α) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illness-induced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNF-α antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNF-α is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development.
PLoS One. 2011 ;6 (5):e19583 21573120
Xiaonan Du, Bobbi Fleiss, Hongfu Li, Barbara D'angelo, Yanyan Sun, Changlian Zhu, Henrik Hagberg, Ofer Levy, Carina Mallard, Xiaoyang Wang
Perinatal Center, Department of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development. Mice were injected intraperitoneally (i.p.) once a day from postnatal day (PND) 3 to PND11 with endotoxin-free saline, a TLR2 agonist Pam(3)CSK(4)(5 mg/kg) or Lipopolysaccharide (LPS, 0.3 mg/kg). Pups were sacrificed at PND12 or PND53 and brain, spleen and liver were collected and weighed. Brain sections were stained for brain injury markers. Long-term effects on memory function were assessed using the Trace Fear Conditioning test at PND50. After 9 days of Pam(3)CSK(4) administration, we found a decreased volume of cerebral gray matter, white matter in the forebrain and cerebellar molecular layer that was accompanied by an increase in spleen and liver weight at PND12. Such effects were not observed in Pam3CSK4-treated TLR 2-deficient mice. Pam3CSK4-treated mice also displayed decreased hippocampus neuronal density, and increased cerebral microglia density, while there was no effect on caspase-3 or general cell proliferation at PND12. Significantly elevated levels of IL-1β, IL-6, KC, and MCP-1 were detected after the first Pam3CSK4 injection in brain homogenates of PND3 mice. Pam(3)CSK(4) administration did not affect long-term memory function nor the volume of gray or white matter. Repeated systemic exposure to the TLR2 agonist Pam(3)CSK(4) can have a short-term negative impact on the neonatal mouse brain.
C-Reactive Protein, Detected with a Highly Sensitive Assay, in Non-Infected Newborns and Those with Early Onset Infection.
Melanie Muenzenmaier, Marita Depperschmid, Christian Gille, Christian F Poets, Thorsten W Orlikowsky
Department of Neonatology, University Childrens' Hospital, Germany.
SUMMARY: BACKGOUND: The aim of this study was to investigate C-reactive protein (CRP), measured by a highly sensitive method (hsCRP) in non-infected newborns and in those with suspected early onset bacterial infection (EOBI) as well as to test whether EOBI would be detectable earlier by hsCRP than by a nephelometric CRP (nsCRP) assay (thresholds > 10 mg/l) or IL-8. PATIENTS AND METHODS: 106 neonates with signs of infection comprised the suspected EOBI group. 134 neonates with risk factors but confirmed exclusion of EOBI served as non-infected controls. RESULTS: In the non-infected group, hsCRP in the first 6 h after birth was low (0.7 mg/l; SD 0.16 mg/l) but showed an increase to 4.11 mg/l (SD 3.33 mg/l) at 72 h (p < 0.001 vs. 6 h). The sensitivity of hsCRP (cut-off 0.3 mg/l) vs. nsCRP for EOBI was 0.46 vs. 0.23 at 6 h after clinical suspicion. Of all parameters measured, IL-8 had the highest sensitivity and specificity to detect EOBI at 6 h (0.60 and 0.90), but declined after 12 and 24 h. CONCLUSION: Lowering the CRP detection threshold by a highly sensitive assay did not improve diagnostic accuracy for EOBI.
Premature infants born after preterm premature rupture of membranes with 24-34 weeks of gestation: a study of factors influencing length of neonatal intensive care unit stay.
Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
OBJECTIVES To determine the factors influencing length of neonatal intensive care unit (NICU) stay among premature infants born after preterm premature rupture of membranes (PPROM) with 24-34 weeks of gestation. METHODS Characteristic parameters of the pregnant women with PPROM and their premature infants were analyzed retrospectively using univariate and multivariate analysis. RESULTS The overall rate of PPROM was 1.3%(323/24,173), of which 19.2%(62/323) were premature infants with sepsis. Overall, the median NICU stay of the premature infants was 11 days. Multiple factor regression analysis identified factors influencing length of stay in premature infants: gestational age (β =-0.172, P = 0.000), parturition modes (β =-0.115, P = 0.000), infant's birth weight (β = -0.728, P = 0.000), infant's discharge weight (β = 0.443, P = 0.000), bacterial culture of cord blood (β =-0.100, P = 0.011) and sepsis (β = 0.192, P = 0.000). Additionally, latency period of sepsis diagnosis in neonatal sepsis between negative and positive cord blood culture was significantly discrepant, and 98.1% specificity and 84.4% positive predictive value for cord blood culture. CONCLUSION We have identified several predictive factors for length of stay in cases of premature infants after PPROM, of which cord blood culture can be used as an additional diagnostic test to detect newborns at risk of infections, and be valuable in clinical application and generalization among neonate sepsis.
A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder.
HQ USAFA/DFB, 2355 Faculty Drive, Suite 2P389, USAF Academy, CO 80840, USA. email@example.com
Autism, an incurable neurodevelopmental brain disorder, is a complex psychopathology in which the affected individual cannot effectively self-regulate their sensory inputs toward coherent and focused motor outputs. There have been many hypotheses as to the etiology of autism - genetics, neurotransmitter imbalances, early childhood immunizations, xenobiotic and teratogenic agents, and maternal infection; the disorder can perhaps be studied best under the field of "Psychoneuroimmunology", which analyzes systemic and psychopathologies from an integrated approach through the combined effects of the nervous, immune, and endocrine systems. Using principles of psychoneuroimmunology along with previously established but yet un-linked scientific principles and observations, this paper proposes a neuroimmune-based mechanistic hypothesis for the etiology of autism that connects elevated levels of maternal pro-inflammatory cytokines to autistic symptoms in her offspring through a logical sequence of events. While both researchers and clinicians often note correlations between pro-inflammatory cytokine levels and autistic symptoms in affected individuals, no specific mechanism has been documented that logically and directly connects the two. I propose that pro-inflammatory cytokines arising from maternal inflammation, infection, and, possibly, autoimmunity, pass through the placenta; enter the fetal circulation; cross the fetal blood-brain barrier (BBB); and cause aberrant neuronal growth and plasticity within the fetal brain via a "cytokine-storm". Microglia and astrocyte stimulation lead to a positive-feedback loop that also facilitates the development of a chronic inflammatory environment within the fetus, pre-disposing it to lifelong comorbid psychiatric and systemic pathologies. Such a mechanism could account for many of the observed symptoms and behaviors of autistic individuals such as hyper-sensitivity to environmental stimuli, object fixation, echolalia, repetitive physical behaviors, chronic enterocolitis, autoimmune disease, and, at the extreme, savantism. The thiazolidinedione pioglitazone (and possibly rosiglitazone), a non-steroidal anti-inflammatory drug (NSAID), which is commonly used to lower blood glucose levels and associated inflammatory markers in patients with diabetes, and histamine receptor blockers, as well as monitoring and limiting sucrose-containing foods, might prove to be effective preventative therapies for the development of autism in the fetus for pregnant women displaying either a cytokine-induced depression or other elevated systemic inflammatory state conditions.
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J Perinatol. 2011 Aug ;31 (8):524-34 21273984
Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns.
J W Logan, T M O'Shea, E N Allred, M M Laughon, C L Bose, O Dammann, D G Batton, K C Kuban, N Paneth, A Leviton
Division of Neonatal-Perinatal Medicine, Betty H Cameron Women's and Children's Hospital, New Hanover Regional Medical Center, Wilmington, NC 28402, USA. firstname.lastname@example.org
OBJECTIVE To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up. STUDY DESIGN The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included:(1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age;(2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders. RESULT Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis. CONCLUSION The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.
Department of Pediatrics (Neonatology), Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, USA. email@example.com
BACKGROUND Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. AIM To identify factors that contribute to brain damage in ELGANs. STUDY DESIGN Multi-center cohort study. SUBJECTS We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. OUTCOME MEASURES Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. RESULTS ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. CONCLUSIONS In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.
Am J Epidemiol. 2008 Aug 27;: 18756016
T F McElrath, J L Hecht, O Dammann, K Boggess, A Onderdonk, G Markenson, M Harper, E Delpapa, E N Allred, A Leviton
Pregnancy Disorders That Lead to Delivery Before the 28th Week of Gestation: An Epidemiologic Approach to Classification.
T F McElrath, J L Hecht, O Dammann, K Boggess, A Onderdonk, G Markenson, M Harper, E Delpapa, E N Allred, A Leviton
Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.
Perinatal Infectious Disease Epidemiology Unit, Hannover Medical School, OE 6415, 30623 Hannover, Germany.
Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common,(2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis,(3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.
Neuroepidemiology Unit, Children's Hospital, Boston, MA, USA.
Biomarkers of inflammation are found in the circulation of adults who have had a stroke. Although these biomarkers may, in part, be indicators of damage, some appear to contribute to damage. Similar biomarkers are found in newborns with cerebral white matter damage or at risk of cerebral palsy. Can we learn about the pathogenesis of neonatal white matter damage from what has been learned about the inflammatory correlates of adult stroke? We discuss relevant findings about systemic inflammatory markers in adult stroke and relate this information to our current understanding of cerebral white matter damage in newborns, especially those born at an extremely low gestational age. We also describe desirable characteristics of future studies of perinatal brain damage that involve measurements of systemic biomarkers.
Department of Neurology, Children's Hospital, Boston, MA 02115, USA. firstname.lastname@example.org
The presence in blood of proteins normally confined to the cytoplasm of brain cells is considered peripheral evidence of brain damage. Only recently have these proteins been measured in the blood of children at risk of brain damage. To show the value and limitations of measuring these proteins, we review their biology and the adult literature that has correlated the blood concentrations of these proteins with lesion size and dysfunction. Conclusion: We conclude that brain damage markers will increasingly be measured in the blood of newborns and other children at risk of brain damage.
Topography of cerebral white-matter disease of prematurity studied prospectively in 1607 very-low-birthweight infants.
K C Kuban, E N Allred, O Dammann, M Pagano, A Leviton, J Share, M Abiri, D Di Salvo, P Doubilet, R Kairam, E Kazam, M Kirpekar, D L Rosenfeld, U M Sanocka, S M Schonfeld
Department of Pediatrics, New England Medical Center, Boston, MA, USA. email@example.com
The objective of this study was to evaluate to what extent (1) the characteristics of localization, distribution, and size of echodense and echolucent abnormalities enable individuals to be designated as having either periventricular hemorrhagic infarction or periventricular leukomalacia and (2) the characteristics of periventricular hemorrhagic infarction and periventricular leukomalacia are independent occurrences. The population for this study consisted of 1607 infants with birthweights of 500 to 1500 g, born between January 1991 and December 1993, who had at least one cranial ultrasound scan read independently by at least two ultrasonographers. The ultrasound data collection form diagrammed six standard coronal views. The cerebrum was divided into 17 zones in each hemisphere. All abnormalities were described as being echodense or echolucent and were classified on the basis of their size, laterality, location, and evolution. Eight percent (134/1607) of infants had at least one white-matter abnormality. The prevalence of white-matter disease decreased with increasing gestational age. Most abnormalities were small or medium sized and unilateral; only large echodensities tended to be bilateral and asymmetric. Large abnormalities, whether echodense or echolucent, were more likely than smaller abnormalities to be widespread, and the extent of cerebral involvement was independent of whether abnormalities were unilateral or bilateral. Large abnormalities were relatively more likely than small abnormalities to involve anterior planes. Small abnormalities, whether echodense or echolucent, or whether unilateral or bilateral, preferentially occurred near the trigone. Using the characteristics of location, size, and laterality/symmetry, we were able to allocate only 53% of infants with white-matter abnormalities to periventricular hemorrhagic infarction or periventricular leukomalacia. Assuming that periventricular leukomalacia and periventricular hemorrhagic infarction are independent and do not share risk factors, and that each occurs in approximately 5% of infants, we would have expected 0.25%, or about 4 individuals, to have abnormalities with characteristics of both periventricular leukomalacia and periventricular hemorrhagic infarction, whereas we found 63 such infants. Most infants with white-matter disease could not be clearly designated as having periventricular hemorrhagic infarction or periventricular leukomalacia only. Periventricular hemorrhagic infarction contributes to the risk of periventricular leukomalacia occurrence, or the two sorts of abnormalities share common risk antecedent factors. The descriptive term echodense or echolucent and the generic term white-matter disease of prematurity should be used instead of periventricular leukomalacia or periventricular hemorrhagic infarction when referring to sonographically defined white-matter abnormalities.
Children's Hospital and Harvard Medical School, Boston, MA, USA.
Support is provided for the hypothesis that activated leukocytes, especially monocytes/macrophages, contribute to cerebral white matter damage in extremely low gestational age newborns. Much of the evidence is indirect and comes from analogies to brain diseases in adults, and from models of brain damage in adult and newborn animals. If the recruitment of circulating cells to the brain contributes to white matter damage in extremely low gestational age newborns, then minimizing the transendothelial migration of circulating cells by pharmacological manipulation might prevent or reduce the occurrence of neonatal white matter damage and the disabilities that follow.
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Department of Anatomy and Cell Biology, University of Melbourne, Vic. 3010, Australia.
A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.
Department of Obstetrics and Gynecology, Klinikum Osnabrück, Osnabrück, Germany.
The bacterial infection of chorion and amnion is a common finding in premature delivery and is referred to as chorioamnionitis. As the mother rarely shows symptoms of a systemic inflammation, the course of chorioamnionitis is frequently asymptomatic and chronic. In contrast, the fetal inflammatory response syndrome represents a separate phenomenon, including umbilical inflammation and increased serum levels of proinflammatory cytokines in the fetus. Ascending maternal infections frequently lead to systemic fetal inflammatory reaction. Clinical studies have shown that antenatal exposure to inflammation puts the extremely immature neonates at a high risk for worsening pulmonary, neurological and other organ development. Interestingly, the presence of chorioamnionitis is associated with a lower rate of neonatal mortality in extremely immature newborns. In the following review, the pathogeneses of inflammation-associated perinatal morbidity are outlined. The concept of fetal multiorganic disease during intrauterine infection is introduced and discussed.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, LLCI 804, New Haven, CT 06520, USA. firstname.lastname@example.org
Intrauterine infection is a unique pathologic process that raises the risk for early-onset neonatal sepsis (EONS). By acting synergistically with prematurity, EONS increases the risk for adverse neonatal outcomes, including intraventricular hemorrhage and cerebral palsy. Although several pathways for the pathogenesis of fetal damage have been proposed, the basic molecular mechanisms that modulate these events remain incompletely understood. Discovery of clinically and biologically relevant biomarkers able to reveal key pathogenic pathways and predict pregnancies at risk for antenatal fetal damage is a priority. Proteomics provides a unique opportunity to fill this gap.
Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.
Lauren M Ellman, Raymond F Deicken, Sophia Vinogradov, William S Kremen, John H Poole, David M Kern, Wei Yann Tsai, Catherine A Schaefer, Alan S Brown
Department of Psychology, Temple University, Philadelphia, PA 19122-6085, United States. email@example.com
Division of Newborn Medicine, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts 02111, USA. firstname.lastname@example.org
Preterm birth can be caused by intrauterine infection and maternal/fetal inflammatory responses. Maternal inflammation (chorioamnionitis) is often followed by a systemic fetal inflammatory response characterized by elevated levels of proinflammatory cytokines in the fetal circulation. The inflammation signal is likely transmitted across the blood-brain barrier and initiates a neuroinflammatory response. Microglial activation has a central role in this process and triggers excitotoxic, inflammatory, and oxidative damage in the developing brain. Neuroinflammation can persist over a period of time and sensitize the brain to subinjurious insults in early and chronic phases but may offer relative tolerance in the intermediate period through activation of endogenous anti-inflammatory, protective, and repair mechanisms. Neuroinflammatory injury not only destroys what exists but also changes what develops.
Increased Maternal/Fetal Blood S100B Levels Following Systemic Endotoxin Administration and Periventricular White Matter Injury in Preterm Fetal Sheep.
Yves Garnier, Alessandro Frigiola, Giovanni Li Volti, Pasquale Florio, Rosanna Frulio, Richard Berger, Stephanie Alm, Monika U von Duering, Audrey B C Coumans, Fernando M Reis, Felice Petraglia, Tom H M Hasaart, Raoul Abella, Hala Mufeed, Diego Gazzolo
Objective. Intrauterine infection is suggested to cause perinatal brain white matter injury. In the current study, we evaluated whether S100B, a brain damage marker, may be also assessed in maternal bloodstream after white matter injury induced by fetal intravenous application of lypopolisaccharide (LPS) endotoxin. Methods. Fourteen fetal sheeps were chronically catheterized at a mean gestational age of 107 days. Three days after surgery, fetuses (n = 7) received 500 ng of LPS or 2 mL 0.9% saline (n = 7) intravenously (IV). Lypopolisaccharide and placebo groups were monitored by continuous hemodynamic data recordings and at 6 predetermined time points (control value; 3, 6, 24, 48, and 72 hours after LPS/placebo administration) blood was drawn for laboratory parameters and S100B assessment. Brain damage was evaluated by light microscopy after Klüver-Barrera staining. Selected areas of the periventricular white matter were also examined by electron microscopy. Results. White matter injury was detected in all LPS-treated fetuses, whereas no abnormalities were seen in control animals or in LPS-treated mothers. Maternal and fetal S100B protein levels were significantly higher in the LPS group than in the control group at all monitoring time points (P <.001). The highest fetal-maternal S100B levels were observed at 3-hour time-point (P <.001). Conclusions. We found that S100B protein is increased in the maternal district in presence of fetal periventricular brain white matter injury induced by endotoxin. The present data offer additional support for S100B assessment in the maternal circulation in pregnancies complicated by intrauterine infection at risk of white matter injury.
The AMPA receptor positive allosteric modulator, S18986, is neuroprotective against neonatal excitotoxic and inflammatory brain damage through BDNF synthesis.
Kim-Da Destot-Wong, Kun Liang, Shailesh Kumar Gupta, Géraldine Favrais, Leslie Schwendimann, Julien Pansiot, Olivier Baud, Michael Spedding, Vincent Lelièvre, Shyamala Mani, Pierre Gressens
Inserm, U676, Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France; PremUP, Paris, France.
Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-willardiine (acting on AMPA-kainate receptors) mimic some aspects of periventricular white matter lesions and neocortical grey matter damage observed in human neonates at risk for developing cerebral palsy. The neonatal mouse brain can be sensitized to excitotoxic damage by IL-1beta exposure similar to that observed in the human situation. Positive modulators of AMPA receptors have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. However whether they can also act as a neuroprotectant in neonatal brain damage has yet to be defined. Therefore the present study uses a well-defined rodent model of neonatal excitotoxic brain lesions to assess the neuroprotective effects of S18986, a positive allosteric modulator of AMPA receptors, as well as its mechanisms of action. In this model, S18986 provided a dose-dependent and long-lasting protection of developing white matter and cortical grey matter against an excitotoxic insult and also when this was combined with a sensitizing inflammatory insult. Neuroprotective effects of S18986 in cortical grey matter involved decreased necrotic and apoptotic cell death. S18986-induced neuroprotection against NMDA receptor-mediated brain lesions was blocked by inhibitors of ERK and PI3 kinase-Akt pathways. S18986 effects were abolished by a neutralizing anti-BDNF antibody and real-time PCR confirmed the stimulation by S18986 of BDNF production in the neonatal brain. The present study provides strong experimental support for the role of S18986 as a candidate molecule for therapy in cases of excitotoxic perinatal brain lesions and identifies BDNF as a key mediator of this S18986-mediated neuroprotection.
Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.
Fadoua Saadani-Makki, Sujatha Kannan, Xin Lu, James Janisse, Elizabeth Dawe, Samuel Edwin, Roberto Romero, Diane Chugani
Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
OBJECTIVE This study was undertaken to determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits. STUDY DESIGN Pregnant New Zealand white rabbits were injected with 1 mL saline solution (n = 8) or 20 microg/kg of lipopolysaccharide in saline solution (n = 8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits (saline solution [n = 30] and lipolysaccharide in saline solution [n = 18] from 4 consecutive litters) underwent neurobehavioral testing. Neonatal brains were stained for microglial cells and myelin. RESULTS Kits in the lipopolysaccharide in saline solution group were hypertonic and demonstrated significant impairment in posture, righting reflex, locomotion, and feeding, along with neuroinflammation indicated by activated microglia and hypomyelination in the periventricular regions. A greater mortality was noted in the lipopolysaccharide in saline solution group (16 stillbirths from 3 litters vs 3 from 1 litter). CONCLUSION Maternal intrauterine endotoxin administration leads to white matter injury and motor deficits in the newborn rabbit, resulting in a phenotype that resembles those found in periventricular leukomalacia and cerebral palsy.
From the INSERM U930 (CIR, JK, SC, ES) and Université François Rabelais (CIR, SC, ES), Tours; INSERM U676 (PO, PG), Faculté de Médecine Denis Diderot, Université Paris 7 (PO, PG), and AP HP (PG), Service de Neurologie Pédiatrique, Hôpital Robert Debré, Paris; and Neonatology Hôpital Clocheville (ES), CHRU Tours, Tours, France.
Intracerebral injection of ibotenate in newborn rodents produces brain damage that mimics that of infants with cerebral palsy. Because maternal infection may contribute to brain injury in preterm infants, we investigated brain damage after maternal inflammation and postnatal ibotenate treatment in a rat model of cerebral palsy. Pregnant rats were injected intraperitoneally with lipopolysaccharide at Days 19 and 20 of gestation. Neonates were given intracerebral injections of ibotenate at postnatal Day 4 and were then killed at Day 9. Lesion sizes were measured by cresyl violet staining, and microglial activation, astrogliosis, and myelination were evaluated by immunohistochemistry. The lipopolysaccharide groups had larger cortical and white matter lesions than the control group; they also had significantly greater microglial activation and astrogliosis and less white matter myelination in the lesioned hemispheres compared with the controls. Thus, maternal endotoxin exposure may affect prenatal development of the offspring and modulate the subsequent development of excitotoxic brain lesions. These results demonstrate the critical influence of prenatal immune events on neonatal central nervous system vulnerability and provide a model for studying the pathophysiology of cerebral damage in preterm infants and, specifically, the interplay between brain inflammation and excitotoxicity.
Department of Anatomy and Cell Biology, University of Melbourne, Victoria 3010, Australia. email@example.com
Abnormal development of the brain during fetal life is now thought to contribute to the aetiology of many functional and behavioural disorders that manifest throughout life. Many factors are likely to underlie such abnormal development including genetic makeup and an adverse intrauterine environment. This review will focus on prenatal hypoxic-ischemic injury and inflammatory/infective insults. A range of experimental models have been used to characterise lesions formed in response to these insults and to determine mechanisms of damage resulting from such events. Relatively brief periods of fetal hypoxia result in neuronal death (cerebellum, hippocampus, and cerebral cortex), white matter damage and reduced growth of neural processes. These effects are more profound at mid than late gestation. Chronic mild placental insufficiency can result in fetal growth restriction and deficits in neural connectivity and myelination. Exposure of the preterm fetus to inflammatory agents causes brain damage particularly in the white matter and this is exacerbated by hypoxia. These studies show that the timing, severity and nature of specific insults are critical in determining the pattern of injury and thus the extent to which neurological function will be affected postnatally. Defining the causes, patterns and mechanisms of brain injury is crucial if we are to develop rational neuroprotective strategies to reduce the burden of altered brain growth and poor functional and behavioural outcomes.