Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection of Hemoglobin

Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and ...

Washington University in St. Louis School of Medicine

Neuronal degeneration following neonatal intraventricular hemorrhage (IVH) is incompletely understood. Understanding the mechanisms of degeneration and cell loss may point toward specific treatments to limit injury. We evaluated the role of hemoglobin (Hb) in cell death after intraventricular injection in neonatal rats. Hb was injected into the right lateral ventricle of post-natal day 7 rats. Rats exposed to anesthesia were used for controls. The CA-1 region of the hippocampus was analyzed via immunohistochemistry, hematoxylin and eosin (H&E) staining, Fluoro-Jade C staining, Western blots, and double-labeling stains. Compared to controls, intraventricular injection of Hb decreased hippocampal volume (27% decrease; p<0.05), induced neuronal loss (31% loss; p<0.01), and increased neuronal degeneration (2.7 fold increase; p<0.01), which were all significantly reduced with the iron chelator, deferoxamine. Hb upregulated p-JNK (1.8 fold increase; p<0.05) and increased expression of the Hb/haptoglobin endocytotic receptor CD163 in neurons in vivo and in vitro (cultured cortical neurons). Hb induced expression of the CD163 receptor, which co-localized with p-JNK in hippocampal neurons, suggesting a potential pathway by which Hb enters the neuron to result in cell death. There were no differences in neuronal loss or degenerating neurons in Hb-injected animals that developed hydrocephalus versus those that did not. Intraventricular injection of Hb causes hippocampal neuronal degeneration and cell loss and increases brain p-JNK levels. p-JNK co-localized with the Hb/haptoglobin receptor CD163, suggesting a novel pathway by which Hb enters the neuron after IVH to result in cell death. 

Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage.

Dermoid cysts are rare congenital teratomas that can occasionally rupture and cause chemical meningitis, neurological deficit, or hydrocephalus. Rarely, dermoid cysts in the pediatric population can rupture spontaneously and even more rarely rupture due to trauma. To date, there are only five documented cases of traumatic rupture of a dermoid cyst. A 2-year-old male presented with 5 days of left eye ptosis and ophthalmoplegia after suffering a fall and was found to have a ruptured left anterior clinoid dermoid cyst that was surgically resected. The patient had significant improvement postoperatively.

Focal traumatic rupture of a dermoid cyst in a pediatric patient: case report and literature review.

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10), SMARCC1 (p = 8.15 × 10), and PTCH1 (p = 1.06 × 10). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Infants then underwent standardized neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd edition at age 2 years, corrected for prematurity. To delineate the effects of brain injury on early hippocampal development, hippocampal volumes were compared across groups and associations between neonatal volumes and neurodevelopmental outcomes at age 2 years were explored. Very preterm infants with brain injury had smaller hippocampal volumes at term equivalent age compared to term and very preterm infants with no to mild injury, with the smallest hippocampi among those with grade III/IV intraventricular hemorrhage and post-hemorrhagic hydrocephalus. Further, larger ventricle size was associated with smaller hippocampal size. Smaller hippocampal volumes were related to worse motor performance at age 2 years across all groups. In addition, smaller hippocampal volumes in infants with brain injury were correlated with impaired cognitive scores at age 2 years, a relationship specific to this group. Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.

Impaired hippocampal development and outcomes in very preterm infants with perinatal brain injury.

Factors associated with syrinx size in pediatric patients undergoing posterior fossa decompression (PFD) or PFD with duraplasty (PFDD) for Chiari malformation type I (CM-I) with syringomyelia (SM; CM-I+SM) are not well established.

Factors associated with syrinx size in pediatric patients treated for Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

Ventriculoperitoneal (VP) shunts are the most common treatment for hydrocephalus in both pediatric and adult patients. Complications resulting from the abdominal portion of shunts include tube disconnection, obstruction of the shunt tip, catheter migration, infection, abdominal pseudocysts, and bowel perforation. However, other less common complications can occur. The authors present a unique case of a patient with a longstanding VP shunt presenting with an acute abdomen secondary to knotting of the peritoneal portion of the catheter tubing.

Case report of mesenteric strangulation secondary to longstanding ventriculoperitoneal shunt catheter.

Hydrocephalus, the abnormal accumulation and impaired circulation/clearance of cerebrospinal fluid, occurs as a common phenotypic feature of a diverse group of genetic syndromes. In this review, we outline the genetic mutations, pathogenesis, and accompanying symptoms underlying syndromic hydrocephalus in the context of: L1 syndrome, syndromic craniosynostoses, achondroplasia, NF 1/2, Down's syndrome, tuberous sclerosis, Walker-Warburg syndrome, primary ciliary dyskinesia, and osteogenesis imperfecta. Further, we discuss emerging genetic variants associated with syndromic hydrocephalus.

Syndromic Hydrocephalus.

Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell-cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH.

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity.

An abnormal or absent superficial abdominal reflex (SAR) may be associated with an underlying spinal cord syrinx. The sensitivity of an abnormal or absent SAR and the relationship to Chiari malformation type I (CM-I) or syrinx morphology has not been studied. We aimed to describe the relationship between SAR abnormalities and syrinx size, location, and etiology. Children who underwent brain or c-spine MRI over 11 years were reviewed in this retrospective cohort study. Patients with idiopathic and CM-I-associated syringes (axial diameter ≥ 3 mm) were included. Clinical examination findings (including SAR) and imaging characteristics were analyzed. Of 271 patients with spinal cord syrinx, 200 had either CM-I-associated or idiopathic syrinx, and 128 of these patients had SAR-evaluation documentation. Forty-eight percent (62/128) had an abnormal or absent reflex. Abnormal/absent SAR was more common in patients with CM-I-associated syrinx (61%) compared with idiopathic syrinx (22%) (P < 0.0001). Abnormal/absent SAR was associated with wider syringes (P < 0.001), longer syringes (P < 0.05), and a more cranial location of the syrinx (P < 0.0001). Controlling for CM-I, scoliosis, age, sex, cranial extent of syrinx, and syrinx dimensions, CM-I was independently associated with abnormal or absent SAR (OR 4.2, 95% CI 1.4-14, P < 0.01). Finally, the sensitivity of SAR for identifying a patient with syrinx was 48.1%. An abnormal/absent SAR was present in most patients with CM-I-associated syrinx but in a minority of patients with idiopathic syrinx. This has implications for pathophysiology of CM-I-associated syrinx and in guiding clinical care of patients presenting with syrinx.

Jennifer M. Strahle

Department of Neurological Surgery,
Department of Orthopedic Surgery,
Department of Pediatrics

Washington University in St. Louis School of Medicine

Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection of Hemoglobin

Jennifer M. Strahle

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Neurological Surgery,Department of Orthopedic Surgery,Department of Pediatrics

Washington University in St. Louis School of Medicine

Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection of Hemoglobin

Department of Neurological Surgery,
Department of Orthopedic Surgery,
Department of Pediatrics