Inflammatory phenomena seem to contribute to the occurrence of perinatal cerebral white matter damage and CP. The stimulus that initiates the inflammation remains obscure. One thousand two hundred forty-six infants born before the 28th postmenstrual week had a protocol ultrasound scan of the brain read concordantly by two independent sonologists. Eight hundred ninety-nine of the children had a neurologic examination at approximately 24-mo postterm equivalent. The placenta of each child had been biopsied under sterile conditions and later cultured. Histologic slides of the placenta were examined specifically for this study. Recovery of a single microorganism predicted an echolucent lesion, whereas polymicrobial cultures and recovery of skin flora predicted both ventriculomegaly and an echolucent lesion. Diparetic CP was predicted by recovery of a single microorganism, multiple organisms, and skin flora. Histologic inflammation predicted ventriculomegaly and diparetic CP. The risk of ventriculomegaly associated with organism recovery was heightened when accompanied by histologic inflammation, but the risk of diparetic CP was not. Low-virulence microorganisms isolated from the placenta, including common skin microflora, predict ultrasound lesions of the brain and diparetic CP in the very preterm infant. Organism recovery does not seem to be needed for placenta inflammation to predict diparetic CP.
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"These microorganisms can initiate an inflammatory response that propagates from the chorioamniotic membranes to the amniotic fluid, and then the fetus (Romero et al., 2007). This fetal involvement, as shown by the so-called 'fetal inflammatory response syndrome', is most clearly associated with adverse neurodevelopmental outcomes such as a very low Bayley mental developmental index at 2 years of age (Kaukola et al., 2006; Korzeniewski et al., 2014; Leviton et al., 2010; Soraisham et al., 2013). "
"Due to its high molecular weight, lipopolysaccharide (LPS), the cell wall component of Gram negative bacteria that initiates the inflammatory cascade, does not cross the healthy placenta well, and the maternal LPS-induced inflammatory response likely differs from the immature fetal response. Because LPS has also recently been found in cord blood in preterm infants with chorioamnionitis  , and microbial invasion of the placenta is present in extremely preterm births , here intra-amniotic injection of LPS was used to model the fetal inflammatory response to bacteria. Transient systemic HI (TSHI) via uterine artery occlusion on embryonic day 18 (E18), neurodevelopmentally equivalent to approximately 25 weeks estimated gestational age (EGA) in humans, induces white matter loss, gliosis and functional deficits in adult rats , and premature loss of the subplate  that mimics many aspects of the pathological abnormalities observed in human post-mortem samples from preterm infants with white matter lesions [35,36] . "
[Show abstract][Hide abstract]ABSTRACT: Background
Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month.
Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction.
Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).
Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.
Full-text · Article · Aug 2014 · Journal of Neuroinflammation
"Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP. Maternal intrauterine infection and inflammation are risk factors for the development of PVL (characterized by focal necrosis around the ventricles, and diffuse microglial and astrocyte activation in the immature WM) and CP in the neonate (Haynes et al, 2003; Leviton et al, 2010). The microglia -immune cells in the brain-, play an important role in remodeling and growth during the fetal and postnatal periods, and they are proposed to be involved in the pathophysiological mechanism for the development of CP in humans. "