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.

Cerebral ischemia or intrauterine inflammation promotes differentiation of oligodendroglial precursors in preterm ovine fetuses: possible cellular basis for white matter injury.

White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion.

Are routine cranial ultrasounds necessary in premature infants greater than 30 weeks gestation?

The purpose of this study was to validate the recommendation of the American Academy of Neurology and the Child Neurology Society that screening cranial ultrasonography be performed routinely on all infants of less than 30 weeks gestation at 7 to 14 days of age and again between 36 and 40 weeks postmenstrual age, and, by using this practice parameter, to determine the number of babies with a clinically significant abnormal screening cranial ultrasound (US) who would otherwise have been missed. A retrospective study of 486 infants of 30 to 33 weeks gestation born January 1, 1999 to June 30, 2004 was done. All had screening cranial ultrasounds. Grade III and/or grade IV intraventricular hemorrhage (IVH) occurred in 4 (0.8%) infants of 30 to 31 weeks gestation. Infants with significant IVH had either risk factors for brain injury or symptoms that would eventually warrant US during their hospitalization. Seven (1.4%) infants had periventricular leukomalacia (PVL). All infants with a final diagnosis of PVL had pre- and/or perinatal risk factors associated with PVL. There was a significant trend toward fewer abnormal cranial ultrasounds from 30 to 33 weeks gestation (p=0.04). Our study supports the recommendation by the American Academy of Neurology and the Child Neurology Society that screening US can be limited but suggests that the gestational age cut off should be 30 weeks or less.

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.

Visual field defects in prematurely born patients with white matter damage of immaturity: a multiple-case study.

PURPOSE: White matter damage of immaturity may affect visual, motor and cognitive functions. This multiple-case study presents standardized perimetry results in six teenagers and young adults born prematurely with visual dysfunction due to white matter damage of immaturity of pre- or perinatal origin. METHODS: Six subjects, aged 13-25 years, born at a gestational age of 28-34 weeks, with white matter damage of immaturity documented by MRI, and optic disc appearances documented by fundus photography, were examined with manual and computerized quantitative perimetry. RESULTS: All subjects had subnormal visual field (VF) function, although the depth and extension of the VF defects differed between subjects. The inferior VF function was more deviant than the superior in all cases. The concordance between the VF defects detected with the different techniques was good, although the static computerized techniques revealed slightly more abnormality. CONCLUSION: White matter damage of immaturity may affect the VF. The lower VF is often more affected than the upper. The abnormalities can be demonstrated by both manual and computerized perimetry.

RetCam image analysis of optic disc morphology in premature infants and its relation to ischaemic brain injury.

AIMS: To assess optic disc characteristics in premature infants with and without ischaemic brain injury and to evaluate the role of optic disc morphology in dating the injury. METHODS: RetCam fundal images, cranial ultrasounds and magnetic resonance imaging (MRI) of 109 premature infants were analysed. The study cohort was divided into subgroups depending on the presence or absence of periventricular leucomalacia (PVL) and intraventricular haemorrhage (IVH). The control group consisted of infants with normal neuroimaging at term and 2 years of age. Using the image analysis software of the RetCam, optic disc diameter (ODD), optic disc area (ODA), and optic cup area (OCA) were measured at 33-34 weeks gestational age. As serial cranial ultrasonography had been performed, it was possible to date the brain injury in those infants with periventricular white matter (PVWM) damage. RESULTS: Although there was a trend towards reducing ODD, ODA, and OCA with increasing severity of IVH, only the IVH 4 group differed significantly from the controls for these parameters (p = 0.002, p = 0.02, and p = 0.04, respectively). 44.4% of infants with grade 4 IVH had small discs. Only one patient had a large cup in a normal sized disc; this patient had IVH 4. In patients with PVWM damage, the median time of insult was 27 weeks in those with small discs and 28 weeks in those with normal discs. This difference was not significant (p = 0.23). CONCLUSIONS: Premature infants with IVH 4 have an increased incidence of optic nerve hypoplasia. We found no association between disc morphology and timing of brain injury.

Contribution of fetal MR imaging in the evaluation of cerebral ischemic lesions.

BACKGROUND AND PURPOSE: Little is known about the different patterns of fetal cerebral ischemic lesions at MR imaging. Our purpose was to evaluate the contribution of MR imaging in the evaluation of such lesions by correlating the results with ultrasonography (US) and neurofetopathologic (NFP) findings. METHODS: We examined 28 fetuses (mean, 28 weeks' gestation) with cerebral ischemic lesions on NFP examination. MR findings were correlated with US and NFP results with regard to the depiction of gyration and parenchymal abnormalities. RESULTS: MR imaging added to US findings in 24 cases by revealing lesions (gyration abnormalities, parenchymal lesions). These results were either overlooked during US (n = 16) or more extensive than expected with US (n = 8). MR findings were always confirmed by NFP. NFP yielded additional findings for 14 lesions that were overlooked during MR imaging (n = 4) or that were more extensive than expected with MR imaging (n = 10). T1-, T2-, and T2*-weighted MR patterns of different lesions (cavitations, gliosis, softening of the white matter, laminar necrosis, calcified leukomalacia, old hemorrhage) were identified. CONCLUSION: MR imaging is a valuable tool in the evaluation of fetal brain ischemia. The results of this study emphasize the role of the different sequences (T1-, T2-, T2*-weighted) required to detect fetal cerebral ischemic lesions. MR imaging is more accurate in the detection of small focal lesions than in the evaluation of diffuse white matter abnormalities.

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.

Optic disc morphology may reveal timing of insult in children with periventricular leucomalacia and/or periventricular haemorrhage.

AIMS: To evaluate the relation between optic disc morphology and timing of periventricular white matter damage, defined as either periventricular leucomalacia (PVL) or periventricular haemorrhage (PVH), as estimated by neuroradiology. METHODS: 35 children with periventricular white matter damage who had had neuroradiology performed and ocular fundus photographs taken had their photographs analysed by digital image analysis and compared with a control group of 100 healthy full term children. Timing of brain lesion was estimated by analysis of the brain lesion pattern on neuroradiological examinations (magnetic resonance imaging or computed tomography). RESULTS: Four of 35 children had a small optic disc area; these four children had a brain lesion estimated to have occurred before 28 weeks of gestation. Nine of 11 children with a large cup area had a PVL/PVH estimated to have occurred after 28 weeks of gestation. The children with PVL/PVH had a significantly larger cup area (median 0.75 mm(2)) than the control group (median 0.33 mm(2)) (p = 0.001) and a significantly smaller neuroretinal rim area (median 1.58 mm(2)) than the controls (median 2.07 mm(2)) (p = 0.001). CONCLUSION: In a child with PVL/PVH and abnormal optic disc morphology, the possibilities of timing of the lesion should be considered.

[Fetal germinal matrix and intraventricular hemorrhage associated with periventricular leukomalacia].

Subependymal germinal matrix hemorrhage with intraventricular hemorrhage(SEIVH) is a common complication associated with delivery in preterm neonates but has rarely been observed in the fetus. We report a fetus with SEIVH, hydrocephalus and periventricular leukomalacia(PVL). Although this fetus had uneventful prenatal periods, transabdominal ultrasound examination(US) at 33 weeks of pregnancy revealed SEIVH and hydrocephalus, and MRI at 36 weeks did associated PVL. While no events reported that could explain the onset of SEIVH, PVL was considered to be the results of anoxic events associated with SEIVH. In addition to US, information provided by fetal MRI, especially T 2-weighted image, permits a better understanding of the pathophysiology of fetal SEIVH with PVL.

Thalamocortical development of parvalbumin neurons in normal and periventricular leukomalacia brains.

To clarify disturbances in higher brain functions including cognition and learning disorders in preterm-born children, we investigated the functional development of the cerebral hemisphere, using parvalbumin (PA) immunohistochemistry in human subjects aged from 21 GW to 11 years of age. PA-immunoreactive neurons first appeared in the RNT at 24 GW, spread to the globus pallidus, and then to the VPoL and VPoM. At 38 GW, PA-immunoreactive neurons first appeared in layer 4 of the primary somatosensory cortex and auditory cortex, and comprised a dense band in layers 4 to 5 at 1 month of age. The developmental changes and course of PA expression in the early developmental stage corresponded to development of the thalamocortical connection and then to the functional development of cortical neurons. In preterm cases, PA expression was decreased in the cerebral cortices that corresponded to widespread or diffuse type PVL, but was increased in those with focal type PVL. These results indicate that accelerated expression of PA was induced by extra-uterine stimuli and a reduction of PA reflects the impairment of thalamocortical neurons.

In utero brain lesions in SIDS.

Serial examination of the cerebral hemispheres of 20 sudden infant death syndrome victims revealed high incidence of leukomalacia (40%), leptomeningeal glioneuronal heterotopias (70%) at the base of the cerebrum, and astrogliosis (65%) in the white matter and medulla reticular formation compared with 20 age-matched controls. These results suggest that an antepartum insult may become an important predisposing risk factor in some patients for sudden infant death syndrome.

Hypoxic-hemodynamic pathogenesis of brain lesions in the newborn.

For more than a century two opposing views on the pathogenetic mechanisms and the timing of the origin of cerebral palsy (CP) have prevailed: the idea first formulated by Little attributing CP to "difficult deliveries" has been opposed by the view by Freud recognizing fetal influences, and the issue seems to be unsettled. The present review seeks to bridge the gap by recognizing that late prenatal or perinatal hypoxic-hemodynamic insult is a dominating final common path in the pathogenesis of static encephalopathies during development, in particular in premature infants. In turn, however, such lesions are determined by early genetic and environmental influences. The pathogenesis of static encephalopathy should therefore be seen as a chain of events, with its origin before gestation.