Chronic inflammation and impaired development of the preterm brain.

The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair.

Single fetal demise in monochorionic pregnancies: incidence and patterns of cerebral injury.

OBJECTIVE: To evaluate the incidence, type and severity of cerebral injury in the surviving monochorionic (MC) cotwin after single fetal demise in twin pregnancies. METHODS: All MC pregnancies with single fetal demise that were evaluated at the Leiden University Medical Center between 2002 and 2013 were included. Perinatal characteristics, neonatal outcome and the presence of cerebral injury, observed on neuroimaging, were recorded for all cotwin survivors. RESULTS: A total of 49 MC pregnancies with single fetal demise, including one MC triplet, were included in the study (n = 50 cotwins). Median gestational age at occurrence of single fetal demise was 25 weeks and median interval between single fetal demise and live birth was 61 days, with a median gestational age at birth of 36 weeks. Severe cerebral injury was diagnosed in 13 (26%) of the 50 cotwins and was detected antenatally in 4/50 (8%) and postnatally in 9/50 (18%) cases. Cerebral injury was mostly due to hypoxic-ischemic injury resulting in cystic periventricular leukomalacia, middle cerebral artery infarction or injury to basal ganglia, thalamus and/or cortex. Risk factors associated with severe cerebral injury were advanced gestational age at the occurrence of single fetal demise (odds ratio (OR), 1.14 (95% CI, 1.01-1.29) for each week of gestation; P = 0.03), twin-twin transfusion syndrome developing prior to single fetal demise (OR, 5.0 (95% CI, 1.30-19.13); P = 0.02) and a lower gestational age at birth (OR, 0.83 (95% CI, 0.69-0.99) for each week of gestation; P = 0.04). CONCLUSIONS: Single fetal demise in MC pregnancies is associated with severe cerebral injury occurring in 1 in 4 surviving cotwins. Routine antenatal and postnatal neuroimaging, followed by standardized long-term follow-up, is mandatory.

Fetal akinesia deformation sequence with delayed skeletal muscle maturation and polymicrogyria: evidence for a hypoxic/ischemic pathogenesis.

Multiple congenital contractures, also known as fetal akinesia deformation sequence (FADS) and related terms, result from decreased fetal movement. The underlying etiologies are diverse and include central nervous system (CNS) dysgeneses and primary myopathies. Persistent central nuclei or the presence of myotubes is often regarded as evidence of a primary myopathic etiology; however, these findings are also associated with impaired fetal innervation. We report 7 fetuses, estimated gestational age 20 to 23 weeks, with persistent myotubular morphology, a change that could be (mis)interpreted as a primary myopathy. In 4 of the patients, CNS histology showed hypoxic/ischemic injury, polymicrogyria, mineralized neurons, and microinfarcts with or without loss of anterior horn neurons. FADS cases with polymicrogyria have frequently been interpreted as a consequence of a primary brain malformation. Only a few descriptions of FADS associate polymicrogyria with CNS hypoxic/ischemic injury, however, and do not describe skeletal muscle maturation delay. We hypothesize that this combination of neural and muscular pathology is an under-recognized pattern in FADS, which results from diffuse hypoxic/ischemic injury involving the brain and spinal cord during early to middle gestation.

Prenatal diagnosis of cerebral lesions acquired in utero and with a late appearance.

Although no precise figures are available, many congenital brain lesions arise from intrauterine disruption, frequently due to obstetric complications. The most common entities include intracranial hemorrhage, ischemic lesions, thrombosis of venous vessels and infections. Accurate prenatal diagnosis is possible in many of these cases. However, the findings may be subtle, particularly in the early stage of the disruptive process. Identification of these conditions requires therefore specific expertise, the combination of fetal neurosonography and magnetic resonance, and frequently there is a need for serial examinations. Targeted diagnostic imaging should be offered to obstetric patients with conditions predisposing to prenatal cerebral insults.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk.

The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

Neonatal loss of gamma-aminobutyric acid pathway expression after human perinatal brain injury.

OBJECT: Perinatal brain injury leads to chronic neurological deficits in children. Damage to the premature brain produces white matter lesions (WMLs), but the impact on cortical development is less well defined. Gamma-aminobutyric acid(GABA)ergic neurons destined for the cerebral cortex migrate through the developing white matter and form the subplate during late gestation. The authors hypothesized that GABAergic neurons are vulnerable to perinatal systemic insults in premature infants, and that damage to these neurons contributes to impaired cortical development. METHODS: An immunohistochemical analysis involving markers for oligodendrocytes, GABAergic neurons, axons, and apoptosis was performed on a consecutive series of 15 human neonatal telencephalon samples obtained postmortem from infants born at 25 to 32 weeks of gestation. The tissue samples were divided into two groups based on the presence or absence of WMLs by performing routine histological analyses. The expression of GABAergic neurons was compared between the two groups by using age-matched samples. Two-tailed t-tests were used for statistical analyses. Ten infants had WMLs and five did not. Significant losses of oligodendrocytes and axons and markedly increased apoptosis were appreciated in tissue samples from the infants with WMLs. Samples from infants with WMLs also showed significant losses of glutamic acid decarboxylase-67-positive cells and calretinin-positive cells, shorter neuropeptide Y-positive neurite lengths, and losses of cells expressing GABA(A)alpha1, GABA(B)R1, and N-acetylaspartate diethylamide NR1 receptors when these factors were compared with those in samples from infants without WMLs (all p < 0.02). CONCLUSIONS: In addition to oligodendrocyte loss, axonal disruption, and excess apoptosis, a significant loss of telencephalon GABAergic neuron expression was found in neonatal brains with WMLs, compared with neonates' brains without WMLs. The loss of GABAergic subplate neurons in infants with WMLs may contribute to the pathogenesis of neurological deficits in children.

Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury.

Although periventricular white matter injury (PWMI) is the leading cause of chronic neurological disability and cerebral palsy in survivors of premature birth, the cellular-molecular mechanisms by which ischemia-reperfusion contributes to the pathogenesis of PWMI are not well defined. To define pathophysiologic relationships among ischemia, acute cerebral white matter damage, and vulnerable target populations, we used a global cerebral ischemia-reperfusion model in the instrumented 0.65 gestation fetal sheep. We developed a novel method to make repeated measurements of cerebral blood flow using fluorescently labeled microspheres to resolve the spatial heterogeneity of flow in situ in three-dimensional space. Basal flow in the periventricular white matter (PVWM) was significantly lower than in the cerebral cortex. During global cerebral ischemia induced by carotid occlusion, flow to all regions was reduced by nearly 90%. Ischemia of 30 or 37 min duration generated selective graded injury to frontal and parietal PVWM, two regions of predilection for human PWMI. Injury was proportional to the duration of ischemia and increased markedly with 45 min of ischemia to extensively damage cortical and subcortical gray matter. Surprisingly, the distribution of PVWM damage was not uniform and not explained by heterogeneity in the degree of white matter ischemia. Rather, the extent of white matter damage coincided with the presence of a susceptible population of late oligodendrocyte progenitors. These data support that although ischemia is necessary to generate PWMI, the presence of susceptible populations of oligodendrocyte progenitors underlies regional predilection to injury.

Roles of the mammalian subventricular zone in cell replacement after brain injury.

The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated.

Fetal trauma: brain imaging in four neonates.

The purpose of this paper is to describe brain pathology in neonates after major traffic trauma in utero during the third trimester. Our patient cohort consisted of four neonates born by emergency cesarean section after car accident in the third trimester of pregnancy. The median gestational age ( n=4) was 36 weeks (range: 30-38). Immediate post-natal and follow-up brain imaging consisted of cranial ultrasound ( n=4), computed tomography (CT) ( n=1) and post-mortem magnetic resonance imaging (MRI) ( n=1). Pathology findings were correlated with the imaging findings ( n=3). Cranial ultrasound demonstrated a huge subarachnoidal hemorrhage ( n=1), subdural hematoma ( n=1), brain edema with inversion of the diastolic flow ( n=1) and severe ischemic changes ( n=1). In one case, CT demonstrated the presence and extension of the subarachnoidal hemorrhage, a parietal fracture and a limited intraventricular hemorrhage. Cerebellar hemorrhage and a small cerebral frontal contusion were seen on post-mortem MRI in a child with a major subarachnoidal hemorrhage on ultrasound. None of these four children survived (three children died within 2 days and one child died after 1 month). Blunt abdominal trauma during pregnancy can cause fetal cranial injury. In our cases, skull fracture, intracranial hemorrhage and hypoxic-ischemic encephalopathy were encountered.

Unilateral schizencephaly and contralateral polymicrogyria associated with umbilical cord mass.

We report a 6-month-old boy with diffuse hypertonia and developmental delay who had unilateral separated-lip schizencephaly and contralateral polymicrogyria. The contralateral polymicrogyria was associated with an incomplete clefting in that hemisphere. An umbilical cord hamartoma is presumed to have caused hypoperfusion to the early developing brain, resulting in bilateral lesions.