[Presumed perinatal ischemic stroke: risk factors and clinical and radiological findings]. / Ictus isquemico presumiblemente perinatal: factores de riesgo, hallazgos clinicos y radiologicos.

INTRODUCTION: Presumed perinatal ischemic stroke is a frequent cause of neurological sequelae. We aimed to describe the different clinical findings and risk factors and to analyse the differences according the vascular origin. PATIENTS AND METHODS: Retrospective, descriptive study of patients diagnosed with presumed perinatal ischemic stroke attended at a tertiary pediatric hospital from 1990 to 2015. RESULTS: 44 patients were included. A total of 24 patients (55%) had arterial ischemic stroke and 20 (45%) had periventricular venous infarction. Delay in diagnosis was significantly higher in patients with periventricular venous infarction compared to those with arterial ischemic stroke (14 and 8 months respectively; p = 0.025). Most patients presented with asymmetrical motor development (90%), only < 5% with seizures or non motor delays. Subsequent epilepsy at follow-up was significantly more prevalent in arterial ischemic stroke group (p = 0.020). We determined risk factors theoretically involved in the pathogenesis of presumed perinatal ischemic stroke: prenatal, obstetrical, perinatal, prothrombotic and cardiac. No significant differences between risk factors and vascular origin were found. Prothrombotic abnormalities were common (48.3%). CONCLUSIONS: Investigation in risk factors implicated in presumed perinatal ischemic stroke is required to develop prevention strategies. Delay in diagnosis is higher in periventricular venous infarction group.

TITLE: Ictus isquemico presumiblemente perinatal: factores de riesgo, hallazgos clinicos y radiologicos.Introduccion. El ictus isquemico presumiblemente perinatal es una causa frecuente de secuelas neurologicas importantes. Los objetivos del estudio son describir las caracteristicas clinicas y los factores de riesgo implicados, y analizar las diferencias segun su origen vascular. Pacientes y metodos. Estudio descriptivo retrospectivo que incluye pacientes con diagnostico de ictus isquemico presumiblemente perinatal atendidos en un hospital terciario entre 1990-2015. Resultados. Se incluyeron 44 pacientes: 24 (55%) fueron de origen arterial, frente a 20 (45%) de origen venoso. El diagnostico fue significativamente mas tardio en los de origen venoso que en los de origen arterial (14 y 8 meses respectivamente; p = 0,025). La mayoria comenzo con un deficit motor (90%), y las crisis epilepticas y el retraso psicomotor global fueron menos frecuentes en ambos grupos (< 5%). La prevalencia de epilepsia posterior fue significativamente mas frecuente entre los de origen arterial (p = 0,020). Se analizaron los factores de riesgo teoricamente implicados en su patogenia: prenatales, obstetricos, perinatales, protromboticos y cardiacos, sin hallarse diferencias significativas en la presencia de estos entre los infartos arteriales y los venosos. Encontramos la presencia de al menos una alteracion en el estudio de hipercoagulabilidad en el 48,3% de los pacientes. Conclusion. Es preciso investigar el papel que desempeñan los factores de riesgo implicados en el ictus isquemico presumiblemente perinatal para establecer medidas preventivas. Su diagnostico es mas tardio si el origen es venoso.

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.

Diffusion MRI findings in monochorionic twin pregnancies after intrauterine fetal death.

BACKGROUND AND PURPOSE: Monochorionic twin pregnancies complicated by the IUFD of 1 twin are associated with substantial morbidity to the survivor twin. The aim of this study was to determine whether fetal sonography, T2 MR imaging, and DWI can diagnose acute cerebral lesions in the survivor of an MC twin pregnancy shortly after fetal death of the co-twin. MATERIALS AND METHODS: During the study period (2007-2010) 34 cases of single IUFD were evaluated. Group A included 6 cases complicated by spontaneous IUFD. Group B had 10 cases of fetal death shortly after treatment of severe TTTS. These were compared with group C, with 18 pregnancies treated by selective termination due to severe complications in MC pregnancies. RESULTS: Altogether 9/34 patients had abnormal prenatal cerebral findings. In group A, in 2/6 of pregnancies with spontaneous death, MR imaging showed findings of severe cerebral infarct, while cerebral damage was not evident by sonography. In another case, the surviving fetus was found to be hydropic on sonography, while MR imaging findings were normal. In group B, in 1/10 cases, cerebral infarct was demonstrated only by DWI. In 2 other cases, sonographic findings were normal, but MR imaging showed germinal matrix bleeding. In group C, in 1/18 cases, only DWI showed bilateral cerebral ischemia. In 2 other cases, MR imaging findings suggested germinal matrix bleeding and focal changes in the basal ganglia. In both cases, fetal sonographic findings were normal. CONCLUSIONS: In our study, early manifestations of cerebral ischemia in monochorionic twin pregnancies were better diagnosed with MR imaging, especially with DWI.

Role of foetal MRI in the evaluation of ischaemic-haemorrhagic lesions of the foetal brain.

OBJECTIVE: The purpose of this study is to define the role of foetal magnetic resonance imaging (MRI) in evaluating cerebral ischaemic-haemorrhagic lesions and the extension of parenchymal injuries. STUDY DESIGN: From September 2006 to September 2010, 271 foetal MRI have been performed on cases referred to us for ultrasound suspect of brain abnormalities or cytomegalovirus infection and Toxoplasma serum conversion. Foetal MRI was performed with a 1.5-T magnet system without mother sedation. RESULTS: Foetal MRI detected ischaemic-haemorrhagic lesions in 14 of 271 foetuses, consisting of 5% incidence. MRI confirmed the diagnosis in three of 14 cases with ultrasonography (US) suspect of ischaemic-haemorrhagic lesions associated with ventriculomegaly. In one of 14 cases with US findings of cerebellar haemorrhage, MRI confirmed the diagnosis and provided additional information regarding the parenchymal ischaemic injury. In eight of 14 cases with US suspect of ventriculomegaly (3), corpus callosum agenesis (2), hypoplasia of cerebellar vermis (1), holoprosencephaly (1) and spina bifida (1), MRI detected ischaemic and haemorrhagic lesions unidentified at US examination. In two of 14 foetuses with US suspect of intracerebral space-occupying lesion, MRI modified the diagnosis to extra-axial haematoma associated with dural sinus malformation. Results were compared with post-mortem findings or afterbirth imaging follow-up. CONCLUSIONS: Foetal MRI is an additional imaging modality in the diagnosis of cerebral ischemic-haemorrhagic lesions, and it is useful in providing further information on the extension of the parenchymal injury and associated abnormalities, thus improving delivery management.

Impact of congenital heart disease on fetal brain development and injury.

PURPOSE OF REVIEW: Advances in cardiac surgical techniques and intensive care have led to improved survival in babies with congenital heart disease (CHD). Although it is true that the majority of children with CHD today survive, many have impaired neurodevelopmental outcome. Although continuing to improve short-term morbidity and mortality are important goals, recent research has focused on defining the impact of CHD on brain development and brain injury in utero. RECENT FINDINGS: The impact of CHD on the developing brain of the fetus and infant will be discussed. Neurologic abnormalities detectable prior to surgery will be described and postnatal progression of abnormalities will be highlighted. Potential causes of these findings will be discussed, including altered cerebral blood flow in utero, and brain development and risk for in-utero and postnatal brain injury. Finally, neurologic and developmental outcome after surgical repair of CHD will be reviewed. SUMMARY: Neurodevelopmental evaluation preoperatively and postoperatively in CHD patients should be standard practice, not only to identify those with impairments who would benefit from intervention services but also to identify risk factors and strategies to optimize outcome. Fetal management and intervention strategies for specific defects may ultimately play a role in improving in-utero hemodynamics and increasing cerebral oxygen delivery to enhance brain development.

Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury.

MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that modulate gene translation. Their expression is altered in many central nervous system (CNS) injuries suggesting a role in the cellular response to stress. Current studies in brain tissue have not yet described the cell-specific temporal miRNA expression patterns following ischemic injury. In this study, we analyzed the expression alterations of a set of miRNAs in neurons and astrocytes subjected to 60 minutes of ischemia and collected at different time-points following this injury. To mimic ischemic conditions and reperfusion in vitro, cortical primary neuronal and astrocytic cultures prepared from fetal rats were first placed in oxygen and glucose deprived (OGD) medium for 60 minutes, followed by their transfer into normoxic pre-conditioned medium. Total RNA was extracted at different time-points after the termination of the ischemic insult and the expression levels of miRNAs were measured. In neurons exposed to OGD, expression of miR-29b was upregulated 2-fold within 6 h and up to 4-fold at 24 h post-OGD, whereas induction of miR-21 was upregulated 2-fold after 24 h when compared to expression in neurons under normoxic conditions. In contrast, in astrocytes, miR-29b and miR-21 were upregulated only after 12 h. MiR-30b, 107, and 137 showed expression alteration in astrocytes, but not in neurons. Furthermore, we show that expression of miR-29b was significantly decreased in neurons exposed to Insulin-Like Growth Factor I (IGF-I), a well documented neuroprotectant in ischemic models. Our study indicates that miRNAs expression is altered in neurons and astrocytes after ischemic injury. Furthermore, we found that following OGD, specific miRNAs have unique cell-specific temporal expression patterns in CNS. Therefore the specific role of each miRNA in different intracellular processes in ischemic brain and the relevance of their temporal and spatial expression patterns warrant further investigation that may lead to novel strategies for therapeutic interventions.

Blockade of PGHS-2 inhibits the hypothalamus-pituitary-adrenal axis response to cerebral hypoperfusion in the sheep fetus.

Decreases in fetal blood pressure stimulate homeostatic stress responses that help return blood pressure to normal levels. Fetal hypothalamus-pituitary-adrenal (HPA) axis responses to hypotension are mediated by chemoreceptor and baroreceptor reflexes and ischemia of the fetal central nervous system. Indomethacin, a nonselective inhibitor of prostaglandin endoperoxide synthase (PGHS)-1 and -2, attenuates the HPA response to hypotension in the fetus. The present study was designed to test the hypothesis that selective inhibition of PGHS-2 also inhibits the HPA response to cerebral hypoperfusion. We studied 13 chronically catheterized fetal sheep (126-136 days gestation). Five fetal sheep were subjected to intracerebroventricular infusion of nimesulide (0.01 mg/day), a specific inhibitor of PGHS-2, and eight were treated with vehicle (DMSO in water) for 5 days. Each fetus was subjected to a 10-min period of brachiocephalic occlusion, which decreased carotid arterial pressure approximately 75% and reflexively increased fetal plasma concentrations of ACTH, POMC, cortisol, and femoral arterial pressure, and decreased fetal heart rate. Nimesulide significantly inhibited the ACTH response to the BCO, while significantly augmenting the reflex cardiovascular response and altering fetal heart rate variability consistent with increased sympathetic nervous system activity. The results of this study demonstrate that the activity of PGHS-2 in the brain is a necessary component of the fetal HPA response to cerebral hypoperfusion in the late-gestation fetal sheep. These results are consistent with those of recent study, in which we demonstrated that the preparturient increase in fetal ACTH secretion depends upon PGHS-2 activity within the fetal brain.

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep.

It is widely hypothesized that accumulation of excitatory amino acids, and oxygen free radicals during or after exposure to hypoxia-ischemia play a pivotal role in preterm periventricular white matter injury; however, there is limited evidence in the intact brain. In preterm fetal sheep (0.65 gestation; term 147 days) we found no significant increase in extracellular levels of excitatory amino acids measured by microdialysis in the periventricular white matter during cerebral ischemia induced by bilateral carotid occlusion. There was no significant change in 8-isoprostane or malondialdehyde levels in the early phase of recovery after occlusion. In contrast, there was a significant delayed increase in most amino acids and in malondialdehyde (but not 8-isoprostane) that was maximal approximately 2-3 days after occlusion. The increase in glutamate was significantly correlated with a secondary increase in cortical impedance, an index of cytotoxic edema, and with white matter damage 3 days post-insult. In conclusion, no significant accumulation of cytotoxins was found within immature white matter during cerebral ischemia. Although a minority of fetuses showed a delayed increase in some cytotoxins, this occurred many days after ischemia, in association with secondary cytotoxic edema, strongly suggesting that these changes are mainly a consequence of evolving cell death.

Contribution of diffusion-weighted imaging in the evaluation of diffuse white matter ischemic lesions in fetuses: correlations with fetopathologic findings.

BACKGROUND AND PURPOSE: The sensitivity of fetal MR imaging is poor with regard to the evaluation of diffuse ischemic white matter (WM) abnormalities. Our purpose was to evaluate the contribution of diffusion-weighted imaging (DWI) in the analysis of microstructural changes in WM and to correlate neuroimaging with neurofetopathologic findings. MATERIALS AND METHODS: We included fetuses with MR imaging, DWI, and a fetopathologic examination. In a region of interest defined by MR imaging, where T1 and T2 intensities were abnormal, the apparent diffusion coefficient (ADC) was measured and immunohistochemical analysis was performed. In fetuses with no WM abnormality in signal intensity, region of interest was defined at random. Histologic reading was performed with a complete blinding of the MR imaging results and ADC values. Three degrees of histologic appearance were defined with regard to vasogenic edema, astrogliosis, microgliosis, neuronal and oligodendrocytic abnormalities, and proliferation or congestion of vessels and were compared with a chi(2) test in groups A (normal ADC) and B (increased ADC) fetuses. RESULTS: We included 12 fetuses in group A and 9 in group B, ranging from 29 to 38 weeks of gestation. All group B fetuses and 1 group A fetus demonstrated WM abnormalities in signal intensity. WM edema and astrogliosis were more common in group B than in group A (7/9 vs 2/12 and 8/9 vs 4/12, respectively). No significant difference was observed between both groups with regard to the other parameters. CONCLUSION: This study showed a strong correlation between increased ADCs and 1) WM abnormalities in signal intensity on MR imaging, and 2) vasogenic edema with astrogliosis of the cerebral parenchyma.

Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion.

The present study tested the effect of ketamine on the fetal reflex responses of late-gestation sheep to brachiocephalic occlusion (BCO), a stimulus that mimics the reduction in cerebral blood flow that results from severe fetal hypotension. Ketamine, a dissociative anesthetic and known noncompetitive antagonist of N-methyl D-aspartate (NMDA) receptors, has previously been shown to impair chemoreceptor responsiveness. Studies from this laboratory suggest that fetal reflex ACTH responses to hypotension are largely mediated by chemoreceptors; therefore, we hypothesized that ketamine would inhibit the reflex hormonal response to BCO. Chronically catheterized fetal sheep were subjected to acute cerebral hypoperfusion through occlusion of the brachiocephalic artery. Fetal blood pressure and heart rate were continuously recorded, and fetal blood samples drawn during the experiment were analyzed with specific hormone assays. Our results demonstrate that ketamine attenuates hemodynamic responses to cerebral hypoperfusion and is a potent inhibitor of ACTH and proopiomelanocortin (POMC)/pro-ACTH release. These data support the hypothesis that fetal reflex responses hypotension are chemoreceptor mediated. Given the potency with which ketamine inhibits ACTH response to fetal hypotension, we suggest that the use of ketamine or other anesthetic or analgesic drugs that block or otherwise interact with the NMDA-glutamate pathways, in late pregnancy or in preterm newborns be reconsidered.

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.

Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep.

In vitro studies suggest that glutamate receptor activation is important in the genesis of post-hypoxic preterm brain injury, but there are limited data on post-hypoxic N-methyl-D-aspartate (NMDA) receptor activation. We therefore examined an infusion of the specific, non-competitive NMDA receptor antagonist dizocilpine (2 mg kg(-1) bolus plus 0.07 mg kg(-1) h(-1) i.v.) from 15 min to 4 h after severe hypoxia-ischemia induced by umbilical cord occlusion for 25 min in fetal sheep at 70% of gestation. Dizocilpine suppressed evolving epileptiform transient activity in the first 6 h after reperfusion (2.3 +/- 0.9 versus 9.3 +/- 2.3 maximal counts min(-1), P < 0.05) and mean EEG intensity up to 11 h after occlusion (P < 0.05). Fetal extradural temperature transiently increased during the dizocilpine infusion (40.1 +/- 0.2 versus 39.3 +/- 0.1 degrees C, P < 0.05). After 3 days recovery, treatment was associated with a significant reduction in neuronal loss in the striatum (31 +/- 7 versus 58 +/- 2%, P < 0.05), expression of cleaved caspase-3 (111+/-7 versus 159 +/- 10 counts area(-1), P < 0.05) and numbers of activated microglia (57 +/- 9 versus 92 +/- 16 counts area(-1), P < 0.05); there was no significant effect in other regions or on loss of immature O4-positive oligodendrocytes. In conclusion, abnormal NMDA receptor activation in the first few hours of recovery from hypoxia-ischemia seems to contribute to post-hypoxic striatal damage in the very immature brain.

Postnatal laboratory timers of antenatal hypoxemic-ischemic brain damage.

OBJECTIVE: Markers were sought to identify the antenatal starting times and rates at which brain damage advanced in children with hypoxemic-ischemic cerebral palsy. STUDY DESIGN: Fetal bradycardia's onset marked the damage's start. Using this baseline, the following were tested as additional timers of the damage's onset: serial blood counts of neonates' normoblasts, platelets, lymphocytes,differences at birth between base excess values in umbilical arterial and venous bloods,brain damage patterns. RESULTS: Each timer had a broad antenatal time frame within which it could identify specific damage starting times. The broad time frames are as follows: Blood lymphocyte counts: 0.45 to 13.8 hours before birth, blood normoblast counts: 0.45 to 55.0 hours before birth, blood platelet counts: 0.5 to >72 hours before birth. Brain damage patterns: 0.4 to >0.7 hour before birth. Hyperventilating and hyperoxygenating neonates greatly accelerated the damage's advance. CONCLUSIONS: Commonly obtained laboratory values and brain images can identify when such brain damage began and the rate at which it advanced.

Perinatal stroke--risk factors and management.

Stroke is an uncommon but increasingly recognised cause of mortality and long-term neurological morbidity in children. A significant number of these events appear to be caused by thromboembolic disease and, as with other childhood thrombotic problems, the incidence of central nervous system events appears highest during the neonatal period. In contrast to peripheral arterial and venous thrombotic problems, it is likely that a proportion of cerebral thromboembolic events occur either in utero or perinatally and reflect different risk factors from those occurring in older infants and children. The pathophysiology of perinatal stroke is complex and in many cases is likely to be multifactorial. It is now recognised that risk factors may relate to both maternal and placental problems as well as fetal and neonatal disorders. Large prospective studies of perinatal stroke are currently lacking and efforts to define the relative contribution from each of these areas are at an early stage. The complex nature of these disorders requires collaboration between a number of different disciplines including obstetrics, fetal medicine, pathology, neonatology and neurology. Of particular interest to haematologists is the possible impact of prothrombotic abnormalities in the pathophysiology of these events and also the potential for the use of antithrombotic agents in both management and prevention.

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.

Role of mitochondrial permeability transition in fetal brain damage in rats.

Recirculation after transient in utero ischemia has previously been found to be accompanied by delayed deterioration of cellular bioenergetic state and of mitochondrial function in the fetal rat brain. Our objective was to assess whether the delayed deterioration is a result of the activation of mitochondrial permeability transition which is observed ultrastructurally as mitochondrial swelling. The respiratory activities and ultrastructure of isolated mitochondria and the cellular bioenergetic state in fetal rat brain were examined at the end of 30 minutes of in utero ischemia and after 1, 2, 3 and 4 hours of recirculation. Cyclosporin A, a potent and virtually specific mitochondrial permeability transition blocker, or vehicle was administered 1 hour after recirculation. In the vehicle-treated animals, the transient ischemia was associated with a delayed deterioration of cellular bioenergetic state and mitochondrial activities at 4 hours of recirculation. The number of swollen mitochondria increased markedly after 4 hours of recirculation. The deterioration and the swelling were prevented by cyclosporin A. The present study indicates that cyclosporin A treatment improves recovery of fetal brain energy metabolism and inhibits the mitochondrial swelling after transient in utero ischemia. The results suggest that mitochondria and mitochondrial permeability transition may be involved in the development of ischemic brain damage in the immature rat.

Central nervous system prostaglandin endoperoxide synthase-1 and -2 responses to oestradiol and cerebral hypoperfusion in late-gestation fetal sheep.

Previous work in this laboratory has demonstrated that cerebral hypoperfusion increases the expression of prostaglandin endoperoxide synthase-2 (PGHS-2) in ovine fetal brain regions. Endogenously produced prostaglandins, in turn, partially mediate the fetal hypothalamus- pituitary-adrenal (HPA) axis response to arterial hypotension. In separate experiments, we have found that oestradiol stimulates fetal HPA axis activity. The present experiments were designed to test the hypothesis that oestradiol increases the expression of PGHS isoforms, and that oestradiol augments the PGHS response to cerebral hypoperfusion. Sixteen fetal sheep of known gestational ages (124-128 days' gestation at the time of study) were subjected to chronic catheterization and implantation of extravascular occluder around the brachiocephalic artery. Eight fetuses were subjected to subcutaneous implantation of a pellet containing 17beta-oestradiol (release rate 5 mg (21 days)-1). Brachiocephalic occlusion (BCO) stimulated adrenocorticotropin (ACTH), cortisol and arginine vasopressin (AVP) secretion, responses that were augmented by oestradiol. One hour after the beginning of a 10 min period of BCO, PGHS-1 mRNA was increased in fetal brainstem and hypothalamus, and PGHS-2 mRNA was increased in fetal brainstem. Oestradiol, by itself, increased the abundance of PGHS-2 mRNA in brainstem and cerebellum, and augmented the PGHS-2 mRNA response to BCO in brainstem. In contrast, oestradiol had no significant effect on the abundance of PGHS-1 mRNA in any brain region. PGHS-1 and PGHS-2 protein levels did not reflect the changes in the respective mRNAs. The abundance of both proteins was increased in cerebral cortex in response to BCO, and the abundance of PGHS-2 protein was increased by both oestradiol and BCO in the hippocampus. The results of this study confirm and extend the results of our previous studies, demonstrating an effect of cerebral hypoperfusion on the expression of both isoforms of PGHS. We conclude that oestradiol increases the expression of PGHS-2 in specific fetal brain regions, and that there is an interaction between oestradiol and BCO in the control of PGHS-2 expression in the fetal brainstem. We expect that at later time-points, the changes in mRNA would be followed by similar changes in enzyme abundance at the protein level. We speculate that at least a part of the effect of oestradiol on fetal HPA axis function is mediated by an interaction between oestradiol and prostaglandin biosynthesis in the fetal brain.

Demonstration of acute ischemic lesions in the fetal brain by diffusion magnetic resonance imaging.

The possibility of detecting acute hypoxic-ischemic brain lesions by prenatal magnetic resonance imaging or ultrasound is low. We present a case of a fetus with a vein of Galen arteriovenous malformation in whom prenatal diffusion-weighted magnetic resonance imaging at 33 weeks of gestation clearly detected cerebral acute ischemic lesions, associated with remarkable decrease of the average apparent diffusion coefficient, whereas T2-weighted imaging was still not informative.

Perinatal asphyxia: timing and mechanisms of injury in neonatal encephalopathy.

This article summarizes the recent medical literature regarding perinatal asphyxia with respect to timing and mechanisms of injury for neonates who were clinically diagnosed with an encephalopathy in the newborn period. Multiple mechanisms of injury are reviewed, including genetic vulnerability, acquired inflammatory responses, and clotting defects that can lead to ischemic-induced brain damage. Before effective treatments for fetal and neonatal brain disorders can be developed, accurate and timely diagnoses of fetal or neonatal brain injury must be achieved. Specific subsets of children can then benefit from neuroprotective strategies that can target the specific developmental aspects of brain adaptation or plasticity relative to the specific etiology and timing of injury after asphyxia.