Development Of Posthemorrhagic Hydrocephalus Research Articles

The role of stem cells in the management of neonatal posthemorrhagic hydrocephalus.

Neonatal intraventricular hemorrhage (IVH) is a common complication of prematurity as it affects 12.4% of preterm infants weighing under 1500g. Posthemorrhagic hydrocephalus (PHH) is an important complication of neonatal IVH and can have serious long-term consequences such as cognitive impairment and cerebral palsy. The purpose of this review is to determine whether stem cell transplantation can play a role in the treatment of neonatal IVH mainly focusing on the prevention of the catastrophic sequelae of neonatal IVH, as well as to the improve outcome of these patients. A literature search was performed using the PubMed/MEDLINE and Scopus databases, and after meticulous screening, eight articles were finally selected. The authors included both animal and human studies in this narrative review. Our review included eight articles, five animal studies and three human studies, including one phase 1 clinical trial, one pilot study, and one case report. Intraventricular transplantation of mesenchymal stem cells (MSCs) early after IVH diagnosis seems to prevent the development of PHH, improve myelination, and reduce periventricular cell death, inflammation, and reactive gliosis. It also seems to be a safe and well-tolerated procedure in preterm infants. Animal and human study findings regarding stem cell transplantation in the treatment of IVH show promising results in reducing the risk of PHH. Further research with larger series is needed to better determine its safety and efficacy. Larger studies such as randomized controlled trials could establish the efficacy and tolerability of the treatment.

Proteomic profile and predictive markers of outcome in patients with subarachnoid hemorrhage

BackgroundThe molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making.MethodsVentricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC).ResultsCSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale.ConclusionsWe here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.

Attenuation of ventriculomegaly and iron overload after intraventricular hemorrhage by membrane attack complex inhibition.

The pathophysiology of posthemorrhagic hydrocephalus (PHH) is not well understood, but recent data suggest blood components play a significant role. This study aimed to understand the timing of membrane attack complex (MAC) activation after intraventricular hemorrhage (IVH) and the effect of MAC inhibition on PHH development. This study was composed of four parts. First, 24 young adult male rats underwent stereotactic intraventricular injection of autologous blood or saline and MRI on day 1, 3, or 7 after hemorrhage. Second, 18 rats underwent intraventricular injection of saline, autologous blood with aurin tricarboxylic acid (ATA) in vehicle, or autologous blood with vehicle and underwent serial MRI studies on days 1 and 3 after hemorrhage. Third, 12 rats underwent intraventricular injections as above and MRI 2 hours after hemorrhage. Finally, 24 rats underwent the intraventricular injections as above, as well as serial MRI studies on days 1, 7, 14, and 28 after hemorrhage. The MR images were used to calculate ventricular volume and iron deposition. Open field testing was performed to assess functional outcomes. Outcomes on day 28 were reported as a ratio to the animal's baseline values and normalized via log-transformation. Statistical analysis included the Shapiro-Wilk tests for normality and t-tests and 1-way analysis of variance for 2 and 3 groups of continuous variables, respectively. MAC was found within the hematoma 1 day after hemorrhage and persisted until day 7. Administration of ATA resulted in similar intraventricular hematoma volumes compared to vehicle 2 hours after hemorrhage. At 1 and 3 days after hemorrhage, ATA administration resulted in significantly smaller ventricular volumes and less hemolysis within the hematoma than in the vehicle animals. Administration of ATA also resulted in significantly smaller ventriculomegaly and less iron deposition in the periventricular area than in the vehicle rats 28 days after hemorrhage. Functionally, ATA rats were significantly faster, traveled longer distances, and spent less time resting than vehicle rats at 28 days. MAC was activated early and persisted within the hematoma until day 7 after IVH. MAC inhibition attenuated hemolysis in the clot and ventriculomegaly acutely after IVH. One month after hemorrhage, MAC inhibition attenuated ventriculomegaly and iron accumulation and improved functional outcomes.

435 Use of Optic Nerve Sheath Diameter in Extraventricular Drain Weaning in Adults With Post-hemorrhagic Hydrocephalus

INTRODUCTION: Optic nerve sheath diameter (ONSD) can be used as a noninvasive measurement of intercranial pressure. Few studies have evaluated the value of ONSD in predicting the need for ventriculoperitoneal shunt (VPS) placement after development of post-hemorrhagic hydrocephalus (PHH) in adults. METHODS: Adult patients 18 years or older, admitted with intracranial hemorrhage and hydrocephalus requiring EVD placement were included in the study. Demographics were recorded. CT imaging of ONSD was measured (mm) upon initial ED visit before EVD placement (pre-EVD), immediately after successful EVD removal (post-EVD), and if applicable, after EVD removal but immediately before VPS placement. Change in ONSD was calculated and groups were stratified by EVD only patients and EVD+VPS patients. RESULTS: Imaging for 30 patients were successfully retrieved and analyzed for bilateral ONSD values at all timepoints. A statistically significant convergence to a normally distributed mean ONSD was found for both groups (EVD and EVD+VPS). Additionally, a statistically significant increase was found in ONSD between the EVD+VPS group compared to the EVD only group. The EVD only group showed a mean EVD placement time of only 14 days (2 weeks) with an average decrease in ONSD (-0.905mm) compared with the EVD+VPS group who had an increase in ONSD at 14-days (+1.089 mm). CONCLUSIONS: Patients with hydrocephalus due to intracranial hemorrhage who went on to require VPS developed an increase in ONSD despite EVD use while patients who were successfully weaned from the EVD developed a decrease in ONSD. ONSD may be a useful adjunct tool to aid in the process of EVD weaning in this patient population.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

Role of N-formyl peptide receptor 2 in germinal matrix hemorrhage: an intrinsic review of a hematoma resolving pathway.

Germinal matrix hemorrhage is one of the leading causes of morbidity, mortality, and acquired infantile hydrocephalus in preterm infants in the United States, with little progress made in its clinical management. Blood clots have been shown to elicit secondary brain injury after germinal matrix hemorrhage, by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development. Current evidence suggests that rapid hematoma resolution is necessary to improve neurological outcomes after hemorrhagic stroke. Various articles have demonstrated the beneficial effects of stimulating the polarization of microglia cells into the M2 phenotype, as it has been suggested that they play an essential role in the rapid phagocytosis of the blood clot after hemorrhagic models of stroke. N-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been shown to be neuroprotective after stroke. FPR2 activation has been associated with the upregulation of phagocytic macrophage clearance, yet its mechanism has not been fully explored. Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor CD36. Scavenger receptor CD36 plays a vital role in microglia phagocytic blood clot clearance after germinal matrix hemorrhage. FPR2 has been shown to phosphorylate extracellular-signal-regulated kinase 1/2 (ERK1/2), which then promotes the transcription of the dual-specificity protein phosphatase 1 (DUSP1) gene. In this review, we present an intrinsic outline of the main components involved in FPR2 stimulation and hematoma resolution after germinal matrix hemorrhage.

Intraventricular hemorrhage in term infants: a single institutional experience between 2016 and 2020.

Intraventricular hemorrhage (IVH) of prematurity is a known complication of preterm birth. Intraventricular hemorrhage in term infants is much less commonly encountered. To address the lack of information in the current literature concerning this demographic, we offer demographic and image findings thatdemonstrate etiology and predict the need for permanent cerebrospinal fluid (CSF) diversion. A prospectively maintained database was queried for all patients with intraventricular hemorrhage from 2016 to 2020 treated at our institution. Demographic data and etiology were collected, along with need for and timing of surgical intervention. A total of 150 IVH patients were identified. Of these patients, 138 were excluded due to prematurity. Twelve patients were born at term with IVH. All patients were followed for at least 8months. Seven patients (58.3%) underwent ventriculoperitoneal (VP) shunt placement, performed between 4days and 4months of age. Superficial siderosis detected by MRI during in-patient stay or follow-up showed a sensitivity of 100% and specificity of 60% for the future development of post-hemorrhagic hydrocephalus (PHH) (p < 0.05). All full-term infants who developed PHH (n = 7, 58.3%) obtained a VP shunt. IVH in term infants occurs infrequently when compared to IVH of prematurity. Etiology of IVH in term infants remains difficult to ascertain, but the majority of patients did demonstrate risk factors. The presence of superficial siderosis on MRI significantly predicted the development of PHH and eventual need for CSF diversion.

Inflammatory Markers as Predictors of Shunt Dependency and Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage

The mechanisms underlying post-hemorrhagic hydrocephalus (PHH) development following subarachnoid hemorrhage (SAH) are not fully understood, which complicates informed clinical decisions regarding the duration of external ventricular drain (EVD) treatment and prevents the prediction of shunt-dependency in the individual patient. The aim of this study was to identify potential inflammatory cerebrospinal fluid (CSF) biomarkers of PHH and, thus, shunt-dependency and functional outcome in patients with SAH. This study was a prospective observational study designed to evaluate inflammatory markers in ventricular CSF. In total, 31 Patients with SAH who required an EVD between June 2019 and September 2021 at the Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark, were included. CSF samples were collected twice from each patient and analyzed for 92 inflammatory markers via proximity extension assay (PEA), and the prognostic ability of the markers was investigated. In total, 12 patients developed PHH, while 19 were weaned from their EVD. Their 6-month functional outcome was determined with the modified Rankin Scale. Of the 92 analyzed inflammatory biomarkers, 79 were identified in the samples. Seven markers (SCF, OPG, LAP TGFβ1, Flt3L, FGF19, CST5, and CSF1) were found to be predictors of shunt dependency, and four markers (TNFα, CXCL5, CCL20, and IL8) were found to be predictors of functional outcome. In this study, we identified promising inflammatory biomarkers that are able to predict (i) the functional outcome in patients with SAH and (ii) the development of PHH and, thus, the shunt dependency of the individual patients. These inflammatory markers may have the potential to be employed as predictive biomarkers of shunt dependency and functional outcome following SAH and could, as such, be applied in the clinic.

Annexin A1 upregulates hematoma resolution via the FPR2/p-ERK(1/2)/DUSP1/CD36 signaling pathway after germinal matrix hemorrhage

Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity and mortality in preterm infants in the United States, with little progress made in its clinical management. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are key contributors towards post-hemorrhagic hydrocephalus development. n-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been associated with the activation of p-ERK1/2, which in turn promotes the transcription of the DUSP1 gene, which may play a role in CD36 signaling. CD36 scavenger, a transmembrane glycoprotein, plays an essential role in microglia phagocytic blood clot clearance after GMH. FPR2's role in blood clot clearance after hemorrhagic stroke is unknown. We hypothesize that FPR2 activation by FPR2 agonist Annexin A1 (AnxA1) will enhance hematoma resolution via the upregulation of the CD36 signaling pathway, thereby improving short- and long-term neurological outcomes. Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in P7 rat pups to induce GMH. AnxA1 and FPR2 Inhibitor (Boc2) were given at 1-h post-GMH via intranasal administration. FPR2 CRISPR was given 48-h prior to GMH induction. Short-term neurological deficits were assessed using negative geotaxis test. Hematoma volume was assessed using hemoglobin assay. Protein expression was assessed using western blots. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests. We have demonstrated that AnxA1 treatment enhances hematoma resolution and improved short and long-term outcomes. Lastly, FPR2 agonist AnxA1 treatment resulted in the upregulation of the FPR2/p-ERK(1/2)/DUSP1/CD36 signaling pathway.

In vitro Investigation of the Role of NCBE in Inflammation Induced Cerebrospinal Fluid Hypersecretion by the Choroid Plexus

Post‐hemorrhagic hydrocephalus (PHH) can be the result of inflammation or deposition of FeCl3 in the choroid plexus (CP) after intraventricular hemorrhage (IVH). The hemorrhage leads to increased CSF secretion from the CP also known as the blood‐CSF‐barrier (BCSFB). The precise molecular mechanism is unknown, but the Na+ dependent Cl‐/HCO3‐ exchanger, NCBE, located in the basolateral membrane of the CP epithelia has been suggested as a possible facilitator of CSF hypersecretion.The aim of this study is to investigate the role of the NCBE located in the CP epithelia after inflammation or deposition of FeCl3in relation to the development of PHH. An in vitro model of the BCSFB was established and validated. The model was generated from mouse pup CP epithelial cells. The cells were treated with either TNF‐□, IL‐1□, LPS or FeCl3. NCBE protein expression of the CP epithelial cells was determined by immunoblotting.The CP epithelial cell cultures showed typical cobblestone‐like morphology, polarization and formed an intermediate tight barrier demonstrated by TEER values of ~ 100 Ω*cm2and expression of tight junctions. Compared with controls TNF‐□ decreased NCBE expression by 23.8 % after 24 h (p=0.0048, n=6/group). IL‐1□ had same effect with 28.3 % decrease after 24 h (p=0.0018, n= 6/group) persisting with a decrease of 88.5 % after 3 and 82.4 % after 7 days (p=0.0004 and p=0.0035, n=6/group). LPS had no effect on NCBE expression(n=5/group). FeCl3 increased NCBE expression by 52 % after 24 h (p=0.024, n=7/group) followed by a decrease of 57.8 % after 7 days (p=0.043, n=3/group).We hypothesized that IVH‐induced CP inflammation or FeCl3deposition leads to hydrocephalus by increasing the expression of the basolateral NCBE in the CP cells which leads to an increased rate of CSF secretion. However, the preliminary results suggest a decrease in expression of NCBE after inflammation whereas only an increase in NCBE expression was seen after FeCl3 deposition.In conclusion, NCBE expression of the CP epithelium in cultures decreases under pro‐inflammatory conditions and increases after FeCl3 deposition. Further studies are needed to define the pathways that lead to regulation of NCBE following hemorrhage.

A Role of Complement in the Pathogenic Sequelae of Mouse Neonatal Germinal Matrix Hemorrhage.

Germinal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia, and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed and characterized a mouse model of GMH based on the injection of collagenase into the subventricular zone of post-natal pups and utilized the model to investigate the role of complement in PHH development. The site-targeted complement inhibitor CR2Crry, which binds deposited C3 complement activation products, localized specifically in the brain following its systemic administration after GMH. Compared to vehicle, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Complement inhibition also improved survival and weight gain, and it improved motor performance and cognitive outcomes measured in adolescence. The progression to PHH, neuronal loss, and associated behavioral deficits was linked to the microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Thus, complement plays an important role in the pathological sequelae of GMH, and complement inhibition represents a novel therapeutic approach to reduce the disease progression of a condition for which there is currently no treatment outside of surgical intervention.

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

BackgroundIntraventricular 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.MethodsCSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons.ResultsCSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 − < 0.0001), LGIVH (p = 0.023 − < 0.0001), and HGIVH (p = 0.015 − 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 − 0.0008) in the whole cohort.ConclusionsCSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition.

Abstract 14028: N-formyl Peptide Receptor 2 Activation via Annexin A1 Up-Regulates Hematoma Resolution After Germinal Matrix Hemorrhage

Introduction: Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, which include cerebral palsy, mental retardation, and post-hemorrhagic hydrocephalus. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are key contributors towards post-hemorrhagic hydrocephalus development. n-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been associated with the activation of scavenger receptor CD36. CD36, a transmembrane glycoprotein, plays an essential role in microglia phagocytic blood clot clearance after GMH. Currently, FPR2’s role in blood clot clearance after hemorrhagic stroke is unknown. Hypothesis: We hypothesize that FPR2 activation by Annexin A1 will enhance hematoma resolution via upregulation of the CD36 signaling pathway, thereby improving short- and long-term neurological outcomes. Methods: Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in male and female P7 rat pups to induce GMH. Annexin A1 and FPR2 Inhibitor (Boc2) were given at 1-hour post-GMH via intranasal administration. Short-term neurobehavior were assessed using negative geotaxis test. Hematoma volume was assessed using hemoglobin assay. Protein expression was assessed using western blots. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests. Nissl staining was conducted on long-term samples to calculate ventricular dilation. Results: We have demonstrated that Annexin A1 treatment decreased hemoglobin content and improved neurobehavior at 72 hours post-ictus. Annexin A1 attenuated post-hemorrhagic hydrocephalus and neurological deficits 4 weeks post-ictus. Lastly, treatment increased FPR2 and CD36 protein expression. Conclusions: This present study demonstrates that FPR2 agonism via Annexin A1 enhances blood clot clearance, thereby improving outcomes after GMH.

Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation and Inhibit the Development of Hydrocephalus After Experimentally Induced Perinatal Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) is a severe complication of preterm birth associated with cerebral palsy, intellectual disability, and commonly, accumulation of cerebrospinal fluid (CSF). Histologically, IVH leads to subependymal gliosis, fibrosis, and disruption of the ependymal wall. Importantly, expression of aquaporin channels 1 and 4 (AQP1 and AQP4) regulating respectively, secretion and absorption of cerebrospinal fluids is altered with IVH and are associated with development of post hemorrhagic hydrocephalus. Human cord blood derived unrestricted somatic stem cells (USSCs), which we previously demonstrated to reduce the magnitude of hydrocephalus, as having anti-inflammatory, and beneficial behavioral effects, were injected into the cerebral ventricles of rabbit pups 18 h after glycerol-induced IVH. USSC treated IVH pups showed a reduction in ventricular size when compared to control pups at 7 and 14 days (both, P < 0.05). Histologically, USSC treatment reduced cellular infiltration and ependymal wall disruption. In the region of the choroid plexus, immuno-reactivity for AQP1 and ependymal wall AQP4 expression were suppressed after IVH but were restored following USSC administration. Effects were confirmed by analysis of mRNA from dissected choroid plexus and ependymal tissue. Transforming growth factor beta (TGF-β) isoforms, connective tissue growth factor (CTGF) and matrix metalloprotease-9 (MMP-9) mRNA, as well as protein levels, were significantly increased following IVH and restored towards normal with USSC treatment (P < 0.05). The anti-inflammatory cytokine Interleukin-10 (IL-10) mRNA was reduced in IVH, but significantly recovered after USSC injection (P < 0.05). In conclusion, USSCs exerted anti-inflammatory effects by suppressing both TGF-β specific isoforms, CTGF and MMP-9, recovered IL-10, restored aquaporins expression towards baseline, and reduced hydrocephalus. These results support the possibility of the use of USSCs to reduce IVH consequences in prematurity.

Thrombocytopenia: is it a prognostic factor for development of post-hemorrhagic hydrocephalus in neonates?

PurposePost-hemorrhagic hydrocephalus (PHH) is a rare but serious complication among premature babies in the neonatal intensive care unit. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. We tried to analyze the risk factors for such complication in our cohort.MethodsWe reviewed our neonatology data bank and included all preterms below 28 weeks who were born in the period between 1999 and 2014 and suffered from an intraventricular hemorrhage (IVH). We reviewed gestational age, gender, birth weight, type of birth, IVH degree, comorbidities, therapy, complications, time to event, protein content of cerebrospinal fluid, and clinical follow-up.ResultsWe identified 180 patients, divided into two subgroups, “B1” with 37 cases (IVH + PHH) and “B2” with 143 cases (IVH − PHH). In group B1, the presence of IVH grades I, II, III, or IV was in 11%, 19%, and 70% respectively. Nineteen patients were treated with a ventricular access device (VAD) or external ventricular drain (EVD). A total of 20 shunts were implanted, with 11 revisions (55%). One patient suffered from thrombocytopenia. In subgroup B2, 51% showed IVH grade I, whereas severe IVH grades were only present in 22%. 25.9% suffered from thrombocytopenia. Thrombocytopenia was significantly higher in patients who did not develop PHH (p value: 0.002).ConclusionAccording to our results, thrombocytopenia could play a decisive role in avoiding development of PHH as a sequel of IVH. We recommend a randomized controlled trial to assess the possible efficacy of antiplatelet drugs in avoiding PHH in this vulnerable group.

Ultrasound-Based Phenotyping of Lateral Ventricles to Predict Hydrocephalus Outcome in Premature Neonates.

Prediction of post-hemorrhagic hydrocephalus (PHH) outcome-i.e., whether it requires intervention or not-in premature neonates using cranial ultrasound (CUS) images is challenging. In this paper, we present a novel fully-automatic method to perform phenotyping of the brain lateral ventricles and predict PHH outcome from CUS. Our method consists of two parts: ventricle quantification followed by prediction of PHH outcome. First, cranial bounding box and brain interhemispheric fissure are detected to determine the anatomical position of ventricles and correct the cranium rotation. Then, lateral ventricles are extracted using a new deep learning-based method by incorporating the convolutional neural network into a probabilistic atlas-based weighted loss function and an image-specific adaption. PHH outcome is predicted using a support vector machine classifier trained using ventricular morphological phenotypes and clinical information. Experiments demonstrated that our method achieves accurate ventricle segmentation results with an average Dice similarity coefficient of 0.86, as well as very good PHH outcome prediction with accuracy of 0.91. Automatic CUS-based ventricular phenotyping in premature newborns could objectively and accurately predict the progression to severe PHH. Early prediction of severe PHH development in premature newborns could potentially advance criteria for diagnosis and offer an opportunity for early interventions to improve outcome.

Treatment of intraventricular hemorrhage in infants

Intraventricular hemorrhage (IVH) is a disorder of the central nervous system, which is most frequently diagnosed in newborns. The disorder occurrence and development are related to the gestation age and weight of a newborn. IVH arises in 30 % of newborns with weight under 1500 g and develops on the 2 nd — 3 rd day after birth. Fifty-five percent of newborns present a neurological deficit following IVH, 30 % of patients with IVH have a permanent disability in early childhood and 70 % — at a different age. Premature newborns with IVH of III–IV grade have a high risk of developing posthemorrhagic hydrocephalus (PHH), cerebral palsy and mental disturbances. Literature review and analysis of the world major medical databases (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, PubMed) of etiology, pathogenesis, treatment of IVH in infants illustrate advantages and limitations of the various methods for the control of intracranial hypertension associated with IVH and PHH. Gold standard and method of permanent control of intracranial hypertension — ventriculoperitoneal shunting frequently requires temporary control of the intracranial pressure and has limitations in this category of patients. Considering that there is no the only correct way of treatment of IVH and PHH, and recognizing disadvantages for each method of temporary and permanent draining of the CSF, the interventions should focus on the early clearing of the CSF pathways. Among proposed techniques, neuroendoscopic lavage is worthy of special attention, because it is associated with a lower rate of infectious complications and need in subsequent neurosurgical interventions according to the research results. Considering the pathogenesis of PHH development and treatment results, techniques of neuroendoscopic lavage need to be further researched and implemented in the list of neurosurgical procedures for the children with IVH in Ukraine.

Posthemorrhagic hydrocephalus development after germinal matrix hemorrhage: Established mechanisms and proposed pathways

In addition to being the leading cause of morbidity and mortality in premature infants, germinal matrix hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

A comprehensive review of therapeutic targets that induce microglia/macrophage-mediated hematoma resolution after germinal matrix hemorrhage.

Currently, there is no effective treatment for germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the germinal matrix, grade II includes intraventricular hemorrhage, grade III includes intraventricular hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

Targeting Germinal Matrix Hemorrhage-Induced Overexpression of Sodium-Coupled Bicarbonate Exchanger Reduces Posthemorrhagic Hydrocephalus Formation in Neonatal Rats.

BackgroundGerminal matrix hemorrhage (GMH) is a leading cause of mortality and lifelong morbidity in preterm infants. Posthemorrhagic hydrocephalus (PHH) is a common complication of GMH. A sodium‐coupled bicarbonate exchanger (NCBE) encoded by solute carrier family 4 member 10 gene is expressed on the choroid plexus basolateral membrane and may play a role in cerebrospinal fluid production and the development of PHH. Following GMH, iron degraded from hemoglobin has been linked to PHH. Choroid plexus epithelial cells also contain iron‐responsive element‐binding proteins (IRPs), IRP1, and IRP2 that bind to mRNA iron‐responsive elements. The present study aims to resolve the following issues: (1) whether the expression of NCBE is regulated by IRPs; (2) whether NCBE regulates the formation of GMH‐induced hydrocephalus; and (3) whether inhibition of NCBE reduces PHH development.Methods and Results GMH model was established in P7 rat pups by injecting bacterial collagenase into the right ganglionic eminence. Another group received iron trichloride injections instead of collagenase. Deferoxamine was administered intraperitoneally for 3 consecutive days after GMH/iron trichloride. Solute carrier family 4 member 10 small interfering RNA or scrambled small interfering RNA was administered by intracerebroventricular injection 24 hours before GMH and followed with an injection every 7 days over 21 days. NCBE expression increased while IRP2 expression decreased after GMH/iron trichloride. Deferoxamine ameliorated both the GMH‐induced and iron trichloride–induced decrease of IRP2 and decreased NCBE expressions. Deferoxamine and solute carrier family 4 member 10 small interfering RNA improved cognitive and motor functions at 21 to 28 days post GMH and reduced cerebrospinal fluid production as well as the degree of hydrocephalus at 28 days after GMH.ConclusionsTargeting iron‐induced overexpression of NCBE may be a translatable therapeutic strategy for the treatment of PHH following GMH.