Intraventricular Hemorrhage and Posthemorrhagic Ventricular Dilation: Current Approaches to Improve Outcomes.

Intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD) are important complications of prematurity with short- and long-term implications for the patient and for nursing care. Several approaches have been shown to reduce the incidence of IVH and, more recently, mitigate the impact of IVH on long-term neurodevelopment. This article discusses the pathophysiology of IVH, with a focus on prevention strategies. Posthemorrhagic ventricular dilation is a common complication of severe IVH and has implications for neurodevelopmental sequelae. Both surgical and nonsurgical interventions for PHVD are described.

Preterm brain injury: Germinal matrix-intraventricular hemorrhage and post-hemorrhagic ventricular dilatation.

Germinal matrix hemorrhage and intraventricular hemorrhages (GMH-IVH) remain a common and clinically significant problem in preterm infants, particularly extremely preterm infants. A large GMH-IVH is often complicated by posthemorrhagic ventricular dilation (PHVD) or parenchymal hemorrhagic infarction and is associated with an increased risk of adverse neurologic sequelae. The widespread use of cranial ultrasonography since the early 1980s has shown a gradual decrease in the incidence of GMH-IVH and has helped with the identification of antenatal and perinatal risk factors and timing of the lesion. The increased use of magnetic resonance imaging (MRI) has contributed to more detailed visualization of the site and extent of the GMH-IVH. In addition, MRI has contributed to the awareness of associated white matter changes as well as associated cerebellar hemorrhages. Although GMH-IVH and PHVD still cannot be prevented, cerebrospinal fluid drainage initiated in the early stage of PHVD development seems to be associated with a better neurodevelopmental outcome. Further studies are underway to improve treatment strategies for PHVD and to potentially prevent and repair GMH-IVH and PHVD and associated brain injury. This chapter discusses the pathogenesis, incidence, risk factors, and management, including preventive measures, of GHM-IVH and PHVD.

Molecular diagnosis of asparagine synthetase (ASNS) deficiency in two Indian families and literature review of 29 ASNS deficient cases.

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.

Congenital Amegakaryocytic Thrombocytopenia Type II Presenting with Multiple Central Nervous System Anomalies.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone marrow failure, caused by MPL gene mutations. The combination of CAMT and central nervous system abnormalities is uncommon. We describe a case with a homozygous missense MPL gene mutation and polymicrogyria, underdevelopment of the cerebellum, and multiple intracranial hemorrhages.

Thromboelastographic profiles of the premature infants with and without intracranial hemorrhage at birth: a pilot study.

OBJECTIVE: To delineate thromboelastographic profiles of the premature infants with and without intracranial hemorrhage during the first 21 days of life. METHODS: In this study, 49 premature infants (24 female; 25 male) were consecutively admitted at our neonatal intensive care unit during a 6 months period were subject to thromboelastography and standard coagulation assessments at birth and weekly up to 21 days. Sixteen out of 49 infants developed intracranial hemorrhage at birth. RESULTS: The test results of 127/196 were considered eligible for analysis. Overall significant changes of the main thromboelastographic parameters were observed shortly after birth. Newborns with intracranial hemorrhage showed increased thromboelastogram-defined thrombin generation (shorter R and time to maximum amplitude times) from birth onward, suggesting a hypercoagulable state. No significant differences concerning thromboelastographic and coagulation assays parameters were found at birth between infants with and without intracranial hemorrhage, except for higher plasma D-Dimer concentration (p = 0.002) in the former infants. Finally, a positive correlation between clot lysis time and gestational age (Spearman's rho = 0.502, p = 0.002) was observed. CONCLUSIONS: Thromboelastographic profiles of the premature infants suggest an effective hemostatic function during the first post-natal weeks. Further study is needed to determine whether thromboelastography may be more useful than coagulation assays to reflect the bleeding risk of the premature infants.

Neuroimaging in the evaluation of neonatal encephalopathy.

BACKGROUND AND OBJECTIVE: Computed tomography (CT) is still used for neuroimaging of infants with known or suspected neurologic disorders. Alternative neuroimaging options that do not expose the immature brain to radiation include MRI and cranial ultrasound. We aim to characterize and compare the use and findings of neuroimaging modalities, especially CT, in infants with neonatal encephalopathy. METHODS: The Vermont Oxford Network Neonatal Encephalopathy Registry enrolled 4171 infants (≥36 weeks' gestation or treated with therapeutic hypothermia) between 2006 and 2010 who were diagnosed with encephalopathy in the first 3 days of life. Demographic, perinatal, and medical conditions were recorded, along with treatments, comorbidities, and outcomes. The modality, timing, and results of neuroimaging were also collected. RESULTS: CT scans were performed on 933 of 4107 (22.7%) infants, and 100 of 921 (10.9%) of those received multiple CT scans. Compared with MRI, CT provided less detailed evaluation of cerebral injury in areas of prognostic significance, but was more sensitive than cranial ultrasound for hemorrhage and deep brain structural abnormalities. CONCLUSIONS: CT is commonly used for neuroimaging in newborn infants with neonatal encephalopathy despite concerns over potential harm from radiation exposure. The diagnostic performance of CT is inferior to MRI in identifying neonatal brain injury. Our data suggest that using cranial ultrasound for screening, followed by MRI would be more appropriate than CT at any stage to evaluate infants with neonatal encephalopathy.

Molecular characterization of factor V leiden G1691A and prothrombin G20210A mutations in Saudi newborns with stroke.

This study examined a possible association between the mutations related to Factor V Leiden and Factor II (prothrombin) and stroke in Saudi neonates. A multiplex PCR was established to detect Factor V Leiden G1691A and prothrombin G20210A mutations in 72 neonatal stroke subjects and 70 healthy adult controls with no family history of thromboembolic diseases. The frequency of the homozygous normal genotype (GG) of both genes was found to be significantly lower in the stroke subjects than in the controls (P < 0.0001). The stroke cases also had higher frequencies of the combined Factor II heterozygous mutant form (GA) and the homozygous normal Factor V (GG) (P < 0.0001) and of the combined heterozygous Factor V and the homozygous normal Factor II genotypes (GG) (P = 0.0) than controls. The study concluded that prothrombin and Factor V Leiden may be important risk factors for neonatal stroke in Saudi children.

Life-threatening intracranial bleeding in a newborn with congenital cytomegalovirus infection: late-onset neonatal hemorrhagic disease.

The authors present a case of a 36-day-old infant with intracranial and intramuscular hemorrhage due to vitamin K deficiency bleeding, who received intramuscular vitamin K prophylaxis at birth. In this case, laboratory tests showed anemia, liver dysfunction with cholestasis, and coagulopathy, consistent with vitamin K deficiency abnormality. Serological analyses showed that cytomegalovirus immunoglobulin (Ig)M and IgG avidity were both positive. The infant was treated successfully with intravenous ganciclovir and blood products. This case suggests that it is imperative to meticulously investigate the etiology in neonates with late-onset hemorrhagic disease of the newborn. Cholestatic liver disease caused by congenital cytomegalovirus infection should be in mind in term infants who presented with late-onset hemorrhagic disease.

Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes.

Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery.

Multiple congenital skull fractures as a presentation of Ehlers-Danlos syndrome type VIIC.

We describe a newborn infant with multiple congenital skull fractures and intracranial hemorrhage. He also had multiple skin folds suggesting a connective tissue abnormality. Electron microscopy of the skin biopsy showed collagen abnormalities with a "hieroglyphic appearance." The analysis of the synthesis of collagen in the cultured dermal fibroblasts demonstrated an accumulation of procollagen I. Molecular analysis found a nonsense mutation Q225X in ADAMTS2 gene, which encodes procollagen I N-terminal proteinase. All these findings confirmed the diagnosis of Ehlers-Danlos syndrome type VIIC (MIM 225410). Family studies suggested a founder effect in Ashkenazi Jews originating from Belarus. Prenatal diagnosis in the subsequent pregnancy reassured the parents that the fetus was an unaffected carrier.

Congenital posthemorrhagic hydrocephalus: a case of fetomaternal alloimmune thrombocytopenia.

Fetal/neonatal alloimmune thrombocytopenia (NAIT) results from fetomaternal mismatch for human platelet alloantigens leading to antibody-mediated destruction of fetal platelets. This is one of the most common causes of severe thrombocytopenia in the newborn with an incidence of 1/800-1,000. In the most severe cases, NAIT may result in intracranial hemorrhage and may lead to death or neurologic sequelae. We report a case of fetal hydrocephalus caused by NAIT and discuss the importance of making an accurate prenatal diagnosis to improve the management of the current pregnancy and the outcome of subsequent pregnancies. Screening of female siblings of affected cases is recommended in order to detect at-risk individuals.

Prenatal demonstration of afferent vessels and progressive thrombosis in a torcular malformation.

OBJECTIVES: To elucidate a part of the prenatal natural history of dural sinus malformation of the posterior fossa. METHODS: Ultrasound and magnetic resonance imaging were performed from 31 to 32 weeks' gestation. RESULTS: We observed the progressive development of a thrombus that was visible as an expanding hyperechoic round area within a cystic mass of the posterior fossa. It was characterized, as expected for a vascular malformation, by the presence of blood flow into the aneurismal cavity. Color doppler identified superior sagittal and straight sinuses, and distinguished that their flow continued into the dilated torcular. Prenatal magnetic resonance imaging confirmed an arteriovenous malformation involving the dural sinus. CONCLUSION: The vascular malformation had a fixed volume and preceded the thrombosis, which formed within several days. The present case is the first report with all the prenatal sonographic features of this condition.

A follow-up study of infants with intracranial hemorrhage at full-term.

OBJECTIVE: To determine physical and cognitive outcomes of full-term infants who suffered intracranial hemorrhage (ICH) at birth. METHODS: A retrospective hospital-based, follow-up study of infants treated in London, Ontario between 1985 and 1996. Follow-up was conducted by telephone interviews and clinic visits. Outcome was measured according to physical and cognitive scales. Perinatal risk factors and hemorrhage characteristics were correlated with final outcome. RESULTS: For this study 66 infants with ICH were identified, of which seven died during the first week of life. We obtained follow-up in all but ten cases (median = 3-years; range 1.0 to 10.9 years). Overall, 57% of infants had no physical or cognitive deficits at follow-up. Death occurred most frequently among those with primarily subarachnoid hemorrhage (19%) and the most favorable outcomes occurred among those with subdural hemorrhage (80% had no disability). In univariate models, thrombocytopenia (platelet count < or = 70 x 10(9)/L), increasing overall hemorrhage severity, frontal location and spontaneous vaginal delivery as opposed to forceps-assisted delivery increased risk for poor outcome. In multivariate models, all these factors tended towards increased risk, but only thrombocytopenia remained significant for physical disability (OR = 7.6; 95% CI = 1.02 - 56.6); thrombocytopenia was borderline significant in similar models for cognitive disability (OR = 4.6; 95% CI = 0.9 - 23.9). CONCLUSION: Although forceps-assisted delivery may contribute to ICH occurrence, our study found better outcomes among these infants than those who had ICH following a spontaneous vaginal delivery. Hemorrhage in the frontal lobe was the most disabling hemorrhage location and if multiple compartments were involved, disability was also more likely to occur. However, in this report we found that the factor that was most likely to contribute to poor outcome was thrombocytopenia and this remained important in multivariate analysis.

Posterior fontanelle sonography: an acoustic window into the neonatal brain.

BACKGROUND AND PURPOSE: Sonographic brain studies are classically performed through the anterior fontanelle, but visualization of posterior supratentorial and infratentorial structures is poor with this approach. Posterior fontanelle sonography is recommended for better assessment of these structures. Our purpose was 1) to determine whether sonography of the brain through the posterior fontanelle (PF) improves visualization of brain lesions when added to the routine anterior fontanelle (AF) approach and 2) to describe standardized PF coronal and sagittal sections. METHODS: In this prospective study (conducted from February 1999 to January 2001), PF sonography was added to AF sonography in 165 consecutive premature neonates with a birth weight of < 2000 g. Sonograms were recorded in digital format for re-evaluation at the end of the study. Lesions were grouped as congenital, infectious, hemorrhagic, or hypoxic-ischemic. The chi2 test for paired data and the kappa coefficient were used to compare diagnoses with AF alone and diagnoses with AF plus PF. RESULTS: PF sonography was performed in 164 of 165 patients. Results were normal in 86 and abnormal in 78. The single posterior fossa malformation detected in this series was best delineated with the PF approach. PF sonography increased the diagnostic rate of grade II hemorrhage by 32%. Cerebellar hemorrhage (two patients) and cerebellar abscesses (one patient) were diagnosed by using the PF approach. PF sonography did not contribute to the diagnosis of periventricular leukomalacia. CONCLUSION: Study of the neonatal brain with the addition of PF sonography afforded greater accuracy in detecting intraventricular hemorrhage compared with AF sonography alone, especially when the ventricle was not dilated. The PF approach better defines posterior fossa malformations.

Major brain lesions detected on sonographic screening of apparently normal term neonates.

Major congenital or acquired structural abnormalities of the brain, with significant prognostic implications have rarely been emphasised in apparently normal infants. Our purpose was to investigate the prevalence and types of major brain lesions in clinically normal term neonates using sonography. From January 1999 to December 2001, we examined 2309 clinically normal term neonates within 3 days of birth. Of these, six (0.26%) had major brain lesions, including three cases of intracerebral haemorrhage (two grade II intraventricular and one temporal lobe haemorrhage), two of corpus callosum agenesis and one lacunar infarct in the territory of the left middle cerebral artery. One child was lost to follow-up, because of adoption, and four had borderline to significant developmental delay at a mean age of 24 months (range 12-36 months). Although the prevalence of major brain lesions was low, these infants have a higher risk of later neurodevelopmental disability, despite an early asymptomatic period. Universal neonatal brain ultrasound screening may help early diagnosis of rare major lesions, some of which have prognostic implications.

D-2-Hydroxyglutaric aciduria with absence of corpus callosum and neonatal intracranial haemorrhage.

We report D-2-hydroxyglutaric aciduria in a neonate with intracranial haemorrhage and absence of the corpus callosum. D-2-hydroxyglutaric acid was confirmed by specific chiral derivatization gas chromatography-mass spectrometry. Absence of the corpus callosum and spontaneous neonatal intracranial haemorrhage should raise the suspicion for metabolic disease, and especially organic acidurias.