Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells.

Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0-60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41-60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.

IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model.

AIMS: Blood clots play the primary role in neurological deficits after germinal matrix hemorrhage (GMH). Previous studies have shown a beneficial effect in blood clot clearance after hemorrhagic stroke. The purpose of this study is to investigate interleukin-19's role in hematoma clearance after GMH and its underlying mechanism of IL-20R1/ERK/Nrf2 signaling pathway. METHODS: A total of 240 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. rIL-19 was administered intranasally 1 hour post-GMH. IL-20R1 CRISPR was administered intracerebroventricularly, or Nrf2 antagonist ML385 was administered intraperitoneally 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, immunohistochemistry, histology, and hemoglobin assay were used to evaluate treatment regiments in the short- and long-term. RESULTS: Endogenous IL-19, IL-20R1, IL-20R2, and scavenger receptor CD163 were increased after GMH. rIL-19 treatment improved neurological deficits, reduced hematoma volume and hemoglobin content, reduced ventriculomegaly, and attenuated cortical thickness loss. Additionally, treatment increased ERK, Nrf2, and CD163 expression, whereas IL-20R1 CRISPR-knockdown plasmid and ML385 inhibited the effects of rIL-19 on CD163 expression. CONCLUSION: rIL-19 treatment improved hematoma clearance and attenuated neurological deficits induced by GMH, which was mediated through the upregulation of the IL-20R1/ERK/Nrf2 pathways. rIL-19 treatment may provide a promising therapeutic strategy for the GMH patient population.

Occipital mass in antenatal sonography.

Biophysical profile (BPP) with ultrasound performed for a 32-year-old G5P3013 admitted at 31 weeks gestation with preterm, premature rupture of membranes (PPROM) noted an extracalvarial mass concerning for an encephalocele. Fetal MRI demonstrated edema over the occiput with no definable lesion visualized. Preterm labor requiring Cesarean delivery resulted in a live male neonate at 33 weeks gestation. An occipital mass was observed on neonatal physical exam. Postnatal ultrasound and MRI were consistent with cephalohematoma. This was surprising given the lack of vaginal delivery. We hypothesize that the occiput was positioned against the maternal ischial tuberosity and developed chronic trauma secondary to normal fetal movement over time, resulting in a cephalohematoma. Postnatal imaging confirmed this diagnosis as the mass gradually decreased and ultimately resolved. Although other etiologies are possible, this case emphasizes the need to consider cephalohematoma in the differential of CNS masses during pregnancy without abdominal trauma and/or vaginal delivery.

Significant intraventricular hemorrhage is more likely in very preterm infants born by vaginal delivery: a multi-centre retrospective cohort study.

OBJECTIVES: The objective of this study is to determine the association between mode of delivery (vaginal delivery [VD] versus cesarean section [CS]) and the rate of significant intraventricular hemorrhage (sIVH) in preterm infants. METHODS: A multicenter retrospective cohort study, based on data collected from the Vermont Oxford Network database. Infants born between 23 and 31+6 weeks of gestational age between 2001 and 2014 were identified. Exposure was the mode of birth (VD versus CS). Primary outcome was development of sIVH. Data were analyzed using univariate and multivariate statistical methods. RESULTS: A total of 1575 infants were eligible. Nine hundred and two infants were born by CS and 673 by VD. Univariable analysis showed that infants born vaginally were more likely to have sIVH (p < .001), die before discharge (p < .001), have a composite poor outcome (death, sIVH or PVL), need oxygen therapy at 36-week corrected gestation (p = .010) and have a longer hospital stay (p = .006). After adjusting for available confounders, multivariable analysis persistently showed that infants between 23 and 27 weeks born by CS were less likely to develop sIVH [OR 1.61 (1.01-2.58), p = .049]. CONCLUSIONS: sIVH is less common in very preterm infants (23-27 weeks of gestation) delivered by CS. However, neurodevelopmental risks associated with survival at this early age, as well as increased maternal morbidities must also be considered.

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding.

RYR1 mutations, the most common cause of non-dystrophic neuromuscular disorders, are associated with the malignant hyperthermia susceptibility (MHS) trait as well as congenital myopathies with widely variable clinical and histopathological manifestations. Recently, bleeding anomalies have been reported in association with certain RYR1 mutations. Here we report a preterm infant born at 32 weeks gestation with arthrogryposis multiplex congenita due to compound heterozygous, previously MHS-associated RYR1 mutations, with additional signs of prenatal hemorrhage. The patient presented at birth with multiple joint contractures, scoliosis, severe thoracic rigidity and respiratory failure. He continued to depend on mechanical ventilation and tube feeding. Muscle histopathology showed a marked myopathic pattern with eccentric cores. Interestingly, the patient had additional unusual prenatal intraventricular hemorrhage, resulting in post-hemorrhagic hydrocephalus as well as epidural hemorrhage affecting the spinal cord. This report adds to the phenotypic variability associated with RYR1 mutations, and highlights possible bleeding complications in affected individuals.

Ventricular Zone Disruption in Human Neonates With Intraventricular Hemorrhage.

To determine if ventricular zone (VZ) and subventricular zone (SVZ) alterations are associated with intraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus, we compared postmortem frontal and subcortical brain samples from 12 infants with IVH and 3 nonneurological disease controls without hemorrhages or ventriculomegaly. Birth and expiration estimated gestational ages were 23.0-39.1 and 23.7-44.1 weeks, respectively; survival ranges were 0-42 days (median, 2.0 days). Routine histology and immunohistochemistry for neural stem cells (NSCs), neural progenitors (NPs), multiciliated ependymal cells (ECs), astrocytes (AS), and cell adhesion molecules were performed. Controls exhibited monociliated NSCs and multiciliated ECs lining the ventricles, abundant NPs in the SVZ, and medial vs. lateral wall differences with a complex mosaic organization in the latter. In IVH cases, normal VZ/SVZ areas were mixed with foci of NSC and EC loss, eruption of cells into the ventricle, cytoplasmic transposition of N-cadherin, subependymal rosettes, and periventricular heterotopia. Mature AS populated areas believed to be sites of VZ disruption. The cytopathology and extension of the VZ disruption correlated with developmental age but not with brain hemorrhage grade or location. These results corroborate similar findings in congenital hydrocephalus in animals and humans and indicate that VZ disruption occurs consistently in premature neonates with IVH.

[Twin pregnancy as the risk factor for neonatal intraventricular hemorrhage]. / Ciaza blizniacza jako czynnik ryzyka wystapienia krwawienia do komór bocznych mózgu u noworodków.

OBJECTIVES: The aim of this study was to find the perinatal risk factors of intravenricular hemorrhage in twin neonates. MATERIAL AND METHODS: A retrospective analysis of 203 twin pregnancies and deliveries between 2003 and 2009 was performed. Then data according birth state and neonatal complications in 406 twins were analyzed. Twin outcome was compared with the outcome of 105 singletons born at the same time and at the same gestational age as twins. RESULTS: Intraventricular hemorrhage was diagnosed in 116/406 (29%) of twins. IVH was found two times more often in the analyzed group than in singletons born at the same gestational age (29% vs. 18%, p = 0,03). In 96% I and II grade hemorrhage was diagnosed and in 4% III and IV grade hemorrhage in the Papille scale was found. CONCLUSIONS: 1) Intraventricular hemorrhage is found more often in twins than in singleton neonates born at the same gestational age. 2) IVH in twins correlate with preterm birth and low birth weight. IVH occur more often in twins with birth weight discordance and with too small maternal weight gain.

Neonatal brain hemorrhage (NBH) of prematurity: translational mechanisms of the vascular-neural network.

Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

Complex congenital heart defect, heterotaxy, imperforate anus, and other congenital anomalies in a 27-week infant: a case study.

According to multiple researchers and studies, congenital heart disease (CHD) occurs in approximately 4.8-12.0 of 1,000 live births in the general population, and 2.4 per 1,000 cases are serious enough to require surgery or cardiac catheterization in the first year of life.1 Historically, it has been assumed that the earlier the gestational age with CHD, the poorer the outcome; however, with continued improvements in neonatal care, this hypothesis should be looked at more closely. This case illustrates the challenges associated with prematurity, complex cardiac defects, intraventricular hemorrhage (IVH), and other congenital anomalies that increase the risk of infection and/or surgical intervention. It will discuss the hospital course of a twin, born at 27 weeks gestation, who was found to have all of these diagnoses, yet, despite the complexity of his case, he had a predominantly uncomplicated hospital course.

Association, among very-low-birthweight neonates, between red blood cell transfusions in the week after birth and severe intraventricular hemorrhage.

BACKGROUND: Previous reports describe a statistical association, among very-low-birthweight (VLBW, <1500 g) neonates, between red blood cell (RBC) transfusion in the first days after birth and development of severe intraventricular (brain) hemorrhage (IVH). STUDY DESIGN AND METHODS: We hypothesized that after we established a neonatal intensive care unit (NICU) transfusion management program in 2009, a decrease in early (first week after birth) RBC transfusion rate and a decrease in the incidence of severe IVH occurred concomitantly. RESULTS: During a 9-year period 2716 VLBW neonates were admitted to our NICUs. In 2004, 58% of VLBW neonates received one or more RBC transfusions during the first week. After a transfusion compliance program was established in 2009, this rate declined, reaching 25% by 2012. In parallel, the severe IVH rate also declined, from 17% in 2004 to 8% in 2012 (R(2) = 0.73). IVH occurred in 27% of those who received a RBC transfusion during the first week versus less than 2% of those with no early transfusion (p < 0.001). The decrease in IVH rate occurred exclusively among neonates born in an Intermountain Healthcare perinatal center and not among those initially cared for in an "outside" hospital and subsequently transported to an Intermountain NICU. CONCLUSIONS: It remains unclear whether transfusing VLBW neonates during the first days after birth is a proximate cause of IVH. However, the present report is consistent with previous studies showing that successful efforts to reduce early RBC transfusions is associated with a decrease in the incidence of severe IVH.

Anaphylactic shock due to vitamin K in a newborn and review of literature.

Newborn infants are born with an immature innate immunity. They are less likely to develop anaphylaxis since their immune system is weaker than older infants and children. There are only a few reports of side effects after vitamin K injection in neonates although prophylaxis against hemorrhagic disease of the newborn with this drug has been in routine practice in all over the world for many years. We herein report a case of anaphylactic shock developing after the intramuscular administration of vitamin K1 in a newborn. To our knowledge, this patient is the first case of neonatal anaphylactic shock developing due to intramuscular administration of vitamin K1. We suggest the clinicians should be aware of this possibility of potentially fatal adverse effect occurring with intramuscular administration of vitamin K1.

Second stage of labor and intraventricular hemorrhage in early preterm infants in the vertex presentation.

OBJECTIVE: To investigate the association between exposure to second stage of labor and duration of second stage, and risk of intraventricular hemorrhage (IVH) among infants delivered <30 weeks of gestation. METHODS: We conducted a retrospective cohort study among 158 singleton vertex deliveries (97 vaginal and 61 cesarean). Multivariable logistic regression was used to evaluate the risk of IVH related to second stage. RESULTS: Infants exposed to second stage as compared to those not exposed to second stage irrespective of their mode of delivery had increased risk of mild IVH (odds ratio [OR] 2.69; 95% confidence interval [CI] 1.15, 6.29) but not of severe IVH (OR 1.14; 95% CI 0.33, 3.84). No relation with risk of mild (OR 0.98; 95% CI 0.95, 1.01) and severe (OR 1.00; 95% CI 0.95, 1.05) IVH was observed for each 1 min increase in duration of second stage. We also observed no significant association between quartiles of duration of second stage and risk of mild (p = 0.20) and severe (p = 0.29) IVH. We did not observe any significant interaction by gestational age, chorioamnionitis, birth weight or presenting complaint on admission. CONCLUSION: The risk of mild IVH was increased in those exposed to a second stage of labor. However, no clear association was observed between duration of second stage and mild or severe IVH.

Epidural hematoma.

Epidural hematomas are rare birth injuries, and spontaneous presentation is exceptional. We present 2 cases of newborns with spontaneous epidural hematomas after delivery. In both cases, cerebral hemorrhage was associated with skull fracture and cephalohematoma. One newborn presented with neurologic symptoms in the form of convulsions, whereas the other was asymptomatic. Confirmation of the diagnosis was made by cranial computed tomography. Both cases were treated surgically by craniotomy. Follow-up showed normal neurologic development.

[Neonatal intracerebral bleeding as initial symptom of gliomatosis cerebri WHO III--neurological outcome after partial hemispherectomy]. / Eine neonatale intrazerebrale Blutung als Initialsymptom einer Gliomatosis cerebri WHO III--neurologisches Outcome nach partieller Hemisphärektomie.

INTRODUCTION: Anaplastic astrocytomas presenting as gliomatosis cerebri in neonates are extremely rare. Tumours in newborns are mostly of neuroectodermal origin. CASE REPORT: We report about a female newborn at term [birth weight 3 600 g (P 90), head circumference 35 cm (P 95) APGAR 9/10/10] with an intracerebral partially clotted bleeding in the left parieto-occipital region. The bleeding was expansive leading to axial and lateral cerebral herniation. The intracerebral bleeding in the left occipital region was surgically removed. Macroscopically no solid tumour was seen, but small fragments of an anaplastic astrocytic tumour (WHO grade III) were diagnosed histologically. After surgery, no remaining tumour was visible in the MRI. 6 weeks later, a recurrent tumour (4×4 cm) was found in the area of the initial bleeding. Further treatment was initially refused by the parents. The child was readmitted to our hospital at the age of 11 months in good clinical condition and presented with left-sided hemiparesis, right-sided hemianopsia and intermittent strabismus convergens alternans. Because of the good clinical condition further therapeutic treatment was initiated. Due to the final extension of the tumour into the temporal, parietal and occipital lobes, a gliomatosis cerebri WHO III was diagnosed. An extended partial hemispherectomy was done. After neurosurgery, no further neurological failures occurred. In the follow-up examination, MRI showed no relapse of the tumour. Chemotherapy according to the HIT SKK protocol was initiated. A relapse did not occur over a follow-up of 2 years. CONCLUSION: This is a rare case report of a congenital gliomatosis cerebri WHO grade III, treated with partial hemispherectomy, leading to a good clinical and neurological long-term outcome.

Perinatal cerebral insults alter auditory event-related potentials.

BACKGROUND: auditory event-related potentials (AERPs) can be used as indices of neural information processing. Altered AERPs have been reported in children and young adults with frontal lobe infarction. AIM: to test the hypothesis that perinatal brain injury affects cortical auditory processing. METHODS: we assessed AERPs at term, 6 and 12months of age in preterm infants [n=9, median gestational age (GA) 27.9, range 23.9-30.0wk], term infants with perinatal intracerebral hemorrhage (ICH) [n=5, GA 40.3, range 37.4-42.3wk], and term infants with perinatal asphyxia [n=4, GA 39.4, range 37.9-40.3wk]. Healthy preterm (n=16) and term infants (n=22) served as controls. A harmonic tone of 500-Hz frequency was used as standard and of 750-Hz as deviant stimulus. Mean AERP amplitudes were calculated over 100ms periods from 50 to 350ms. The developmental outcome was followed until 2years of age. RESULTS: the term ICH (p=0.012) and asphyxia (p=0.0016) group had smaller or more negative responses to the deviant, resulting in smaller or more negative MMR amplitudes than those of the controls. The preterm ICH group did not differ significantly from their preterm born controls. MMR varied in all patient groups and was not associated with adverse outcome. CONCLUSION: AERP alterations suggest that perinatal cerebral insults affect cortical auditory processing.

A new method to analyse the pace of child development: Cox regression validated by a bootstrap resampling procedure.

BACKGROUND: Various perinatal factors influencing neuromotor development are known from cross sectional studies. Factors influencing the age at which distinct abilities are acquired are uncertain. We hypothesized that the Cox regression model might identify these factors. METHODS: Neonates treated at Aachen University Hospital in 2000/2001 were identified retrospectively (n = 796). Outcome data, based on a structured interview, were available from 466 children, as were perinatal data. Factors possibly related to outcome were identified by bootstrap selection and then included into a multivariate Cox regression model. To evaluate if the parental assessment might change with the time elapsed since birth we studied five age cohorts of 163 normally developed children. RESULTS: Birth weight, gestational age, congenital cardiac disease and periventricular leukomalacia were related to outcome in the multivariate analysis (p < 0.05). Analysis of the control cohorts revealed that the parents' assessment of the ability of bladder control is modified by the time elapsed since birth. CONCLUSIONS: Combined application of the bootstrap resampling procedure and multivariate Cox regression analysis effectively identifies perinatal factors influencing the age at which distinct abilities are acquired. These were similar as known from previous cross sectional studies. Retrospective data acquisition may lead to a bias because the parental memories change with time. This recommends applying this statistical approach in larger prospective trials.

Coagulation abnormalities and severe intraventricular hemorrhage in extremely low birth weight infants.

BACKGROUND: The association between intraventricular hemorrhage (IVH) and coagulation in infants has been a subject of controversy. Only few publications assessing risk factors for development of IVH reported results of coagulation studies. OBJECTIVES: To evaluate the levels of coagulation and fibrinolysis systems in ELBW infants and determine their influence on IVH. PATIENTS AND METHODS: Following IRB approval coagulation status of 38 ELBW infants was evaluated on first and second day of life. Severity of IVH assessed by cerebral ultrasonography was graded according to Papile classification. Newborns were assigned to either Group A--Grade III or IV, or Group B--Grade I-II, or no IVH. RESULTS: Neonates with Grade III/IV IVH had significantly lower plasma Factor VII (FVII) level on first day of life and FVII differed significantly between Groups A and B with sensitivity of 100%, specificity 41% for a cut-off value of< 7%. In Group A there was no improvement of prothrombin and activated partial thromboplastin times on Day 2. A significant decline of platelet count was also observed. CONCLUSIONS: High-grade IVH coincides with severe derangement of coagulation in ELBW infants with FVII level being the most sensitive, it is not clear what the reason for such low FVII concentration is. Further studies are indicated.

[Intracerebral bleeding as the first symptom of a congenital anaplastic astrocytoma]. / Eine intrazerebrale Blutung als Initialsymptom eines konnatalen anaplastischen Astrozytoms.

BACKGROUND: Anaplastic astrocytomas in neonates are extremely rare. Newborns, however, often have neuroectodermal central nervous tumours. CASE REPORT: We report about a female term newborn (birth weight 3,600 g, APGAR 9/10/10), who had shrill screams, intermittent shivering and bradycardia. An ultrasound scan of the brain showed an intracerebral bleeding. Therefore, the child was transferred to the intensive care unit of our hospital. A CT scan showed cerebral bleeding in the left parieto-occipital region, partially clotted, with a space-demanding effect. The intracerebral bleeding in the left occipital region was cleared out. No tumour was found, but an anaplastic astrocytoma (WHO Grade III) was diagnosed histologically. Serial ultrasound investigations of the brain showed a normal midline and a redevelopment of the left-sided ventricle. After surgery no tumour was visible in the MRI. Six weeks later, a tumour was found in the area of the initial bleeding region on MRI. CONCLUSION: Congenital anaplastic astrocytomas have a variable outcome, with different survival rates as compared to adults. In the literature, survival rates of 36-50 % were found after complete tumour resection. In cases of neonatal intracerebral bleeding, a tumour might be the cause of the haemorrhage.

[Evaluation of malformations of the fetal central nervous system using fetal MRI]. / Das fetale MRT in der pränatalen Beurteilung von ZNS-Störungen.

PURPOSE: Ultrasound as the primary prenatal screening modality is used to detect fetal anomalies. Aim of the study was to prove the additional value of fetal magnetic resonance imaging (MRI). MATERIALS AND METHODS: In 25 pregnant women (age 30.6 +/- 4.8; 24 single and one twin pregnancy) with pathologic findings of the central nervous system detected by obstetric ultrasound, a fetal MRI was performed. All sequences (T2w-HASTE, TRUEFISP, T 1w-FLASH 2D, DWI) were performed using the breath-hold technique. The results were compared to postnatal MRI or ultrasound scan findings and tested for correlation with the clinical course and development of these children. RESULTS: Three to seven days after ultrasound, an MRI of all 26 fetuses without sedation was performed (26.6 +/- 4.0 GW). One healthy twin was not included in this study. MRI confirmed the ultrasonographic diagnosis in 7 cases. Compared to ultrasound, an additional pathology could be detected by MRI in 8 cases. In 10 cases ultrasound diagnosis was overruled by MRI. Prenatal MRI findings were confirmed by postnatal imaging in 18 children. The clinical course was predictable in 8 of 15 cases, depending on the pathology detected. Three newborns died in the perinatal period. CONCLUSION: Our results showed that fetal MRI has a high impact as an addition to ultrasound in evaluating congenital CNS pathology. Fetal MRI has become a helpful device for advising parents. However, clinical course and development still cannot be predicted based on MRI findings alone.