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

BACKGROUND: The 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. METHODS: Ventricular 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). RESULTS: CSF 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. CONCLUSIONS: We 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.

Use of an Irrigating External Ventricular Drain in an Infant: Proof-Of-Concept Technical Note.

OBJECTIVE: This report describes the procedural nuances for use of an irrigating external ventricular drain (EVD) in an infant patient. Intraventricular hemorrhage (IVH) and other intraventricular pathologies, such as infection, can occur in a variety of situations and patient populations, with few interventions available for immediate resolution. While manual endoscopic surgical irrigation has been trialed in both adult and pediatric patient populations to clear blood products or debris, this concept has recently been further extrapolated to the use of a continuous irrigating EVD over a more extended period. While this technique has been more commonly used for subarachnoid hemorrhage in adults, study of its use in pediatric patients, particularly in infants, is lacking. METHODS: In this single case technical note of proof of feasibility, a continuous irrigating EVD was used in an infant to help clear an iatrogenic IVH. RESULTS: Utilization of an irrigating EVD was successfully completed in a 9 kg infant without associated complications. Clearance of IVH was noted after 9 days of irrigation. CONCLUSIONS: Use of irrigating EVD catheters should not be limited to the adult population. Indications for use are broad in the pediatric population and warrant further exploration.

Current Status and Associated Factors of Post-Hemorrhagic Hydrocephalus in Infants of 22 to 28 Weeks Gestation With Severe Intraventricular Hemorrhage in Korea: A Nationwide Cohort Study.

BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Distinct Cerebrospinal Fluid Lipid Signature in Patients with Subarachnoid Hemorrhage-Induced Hydrocephalus.

Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic's landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.

CSF hypersecretion versus impaired CSF absorption in posthemorrhagic hydrocephalus: a systematic review.

BACKGROUND: The molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) remain elusive. The aim of this systematic review was to evaluate existing literature on increased CSF secretion and impaired CSF absorption as pathogenic contributors to CSF accumulation in neonatal and adult PHH. METHODS: The systematic review was conducted in accordance with the PRISMA guidelines. Relevant studies published before March 11th, 2023, were identified from PubMed and reference lists. Studies were screened for eligibility using predefined inclusion and exclusion criteria. Data from eligible studies were extracted and potential sources of bias were evaluated. RESULTS: Nineteen studies quantified CSF production rates and/or CSF absorption capacity in human patients with PHH or animals with experimentally induced PHH. Increased CSF production was reported as early as 24 h and as late as 28 days post ictus in six out of eight studies quantifying CSF production rates in animals with experimentally induced PHH. Impaired CSF absorption was reported in all four studies quantifying CSF absorption capacity in human patients with PHH and in seven out of nine studies quantifying CSF absorption capacity in animals with experimentally induced PHH. Impaired CSF absorption was reported as early as 30 min and as late as 10 months post ictus. CONCLUSIONS: The pathological CSF accumulation in PHH likely arises from a combination of increased CSF secretion and impaired CSF absorption, which may manifest at different time scales following a hemorrhagic event. Emergent evidence on increased CSF secretion by the choroid plexus may herald a paradigm shift in our understanding of PHH.

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.

Therapeutic strategies to recover ependymal barrier after inflammatory damage: relevance for recovering neurogenesis during development.

The epithelium covering the surfaces of the cerebral ventricular system is known as the ependyma, and is essential for maintaining the physical and functional integrity of the central nervous system. Additionally, the ependyma plays an essential role in neurogenesis, neuroinflammatory modulation and neurodegenerative diseases. Ependyma barrier is severely affected by perinatal hemorrhages and infections that cross the blood brain barrier. The recovery and regeneration of ependyma after damage are key to stabilizing neuroinflammatory and neurodegenerative processes that are critical during early postnatal ages. Unfortunately, there are no effective therapies to regenerate this tissue in human patients. Here, the roles of the ependymal barrier in the context of neurogenesis and homeostasis are reviewed, and future research lines for development of actual therapeutic strategies are discussed.

Neurodevelopmental outcomes of neonatal posthemorrhagic hydrocephalus and psychological effects on the parents.

BACKGROUND: Neonatal posthemorrhagic hydrocephalus remains a common complication in preterm infants, with high rates of mortality and morbidity, placing parents at high risk of anxiety and depression. We sought to investigate the neurodevelopmental outcomes of infants with posthemorrhagic hydrocephalus who underwent surgery and the psychological effect on their parents. METHODS: We retrospectively analysed all infants with posthemorrhagic hydrocephalus born between 2014 and 2020 in the Children's Hospital of Chongqing Medical University, China. The neurodevelopmental outcomes of 28 patients were evaluated by the Pediatric Stroke Outcome Measure score, and the psychological states of the parents of survivors were assessed by the Hospital Anxiety and Depression Scale. RESULTS: The families of the 28 patients were followed up for a median duration of 3 years; 6 (21.4%) patients died within 6 months after discharge, 12 (42.9%) patients had moderate to severe dysfunction, and only 10 (35.7%) patients had good outcomes. Regarding the 22 parents of the survivors, 5 (22.7%) and 4 (18.2%) had borderline anxiety and depression symptoms, respectively. Two (9.1%) caregivers had exact anxiety and depression symptoms. Leukomalacia after intraventricular haemorrhage was associated with adverse neurological outcomes. The infants' histories of epileptic seizures during the neonatal period were associated with the anxiety of their parents. CONCLUSION: The overall outcome of posthemorrhagic hydrocephalus patients is unsatisfactory, and children with leukomalacia after haemorrhage tend to have poor outcomes. A history of epileptic seizures during the course of the disease may exacerbate the anxiety of the caregivers.

Permanent Surgical Treatment for Posthemorrhagic Hydrocephalus in Preterm Infants.

While the standard management for posthemorrhagic hydrocephalus (PHH) has not been determined, many patients initially receive temporary treatment such as a ventricular drainage, a ventricular reservoir, or a ventriculosubgaleal shunt. Subsequently, approximately 15% of patients with PHH will require permanent cerebrospinal fluid diversion. Shunt placement is most commonly performed for PHH as permanent treatment. However, shunting still has high complication rates. Since the development of the neuroendoscopic technique has progressed, and indication has been expanded, endoscopic third ventriculostomy with or without choroid plexus cauterization has performed more frequently in recent years in patients with PHH. In this paper, the permanent treatment for PHH will be reviewed based on the latest evidence.

Variability in neurosurgical management and associated comorbidities and complications among preterm patients with posthemorrhagic hydrocephalus in the United States.

OBJECTIVE: Posthemorrhagic hydrocephalus (PHH) remains a major morbidity of premature birth resulting from intraventricular hemorrhage (IVH). National consensus guidelines for the timing of surgical interventions are lacking, which leads to considerable variations in management among neonatal intensive care units (NICUs). Early intervention (EI) has been shown to improve outcomes, but the authors hypothesized that the timing from IVH to intervention affects the comorbidities and complications associated with PHH management. The authors used a large national inpatient care data set to characterize comorbidities and complications associated with PHH management in premature infants. METHODS: The authors used hospital discharge data from the 2006-2019 Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) to conduct a retrospective cohort study of premature pediatric patients (weight < 1500 g) with PHH. The predictor variable was the timing of the PHH intervention (EI ≤ 28 days vs late intervention [LI] > 28 days). Hospital stay data included hospital region, gestational age, birth weight (BW), length of stay (LOS), PHH treatment procedures, comorbidities, surgical complications, and death. Statistical analysis included chi-square and Wilcoxon rank-sum tests, Cox proportional hazards regression, logistic regression, and a generalized linear model with Poisson and gamma distributions. Analysis was adjusted for demographic characteristics, comorbidities, and death. RESULTS: Of the 1853 patients diagnosed with PHH, 488 (26%) had documented timing of surgical interventions during their hospital stay. More patients had LI than EI (75%). The patients in the LI group of patients had younger gestational age and lower BW. There were significant regional differences in the timing of treatment: hospitals in the West performed EI, whereas hospitals in the South performed LI, even after adjustment for gestational age and BW. The LI group was associated with longer median LOS and more total hospital charges compared with the EI group. More temporary CSF diversion procedures occurred in the EI group, whereas more permanent CSF-diverting shunts were placed in the LI group. Shunt/device replacement and complications did not differ between the two groups. The LI group had 2.5-fold higher odds of sepsis (p < 0.001) and almost 2-fold higher odds of retinopathy of prematurity (p < 0.05) than the EI group. CONCLUSIONS: The timing of PHH interventions differs by region in the United States, whereas the association of potential benefits with treatment timing suggests the importance of national consensus guidelines. Development of these guidelines can be informed by data regarding treatment timing and patient outcomes available in large national data sets, which provide insights into comorbidities and complications of PHH interventions.

Can ventricular 3D ultrasound of neonates with posthemorrhagic hydrocephalus inform on the need for a ventriculoperitoneal shunt?

OBJECTIVE: Some neonates born prematurely with intraventricular hemorrhage develop posthemorrhagic hydrocephalus and require lifelong treatment to divert the flow of CSF. Early prediction of the eventual need for a ventriculoperitoneal shunt (VPS) is difficult, and early discussions with families are based on statistics and the grade of hemorrhage. The authors hypothesize that change in ventricular volume during ventricular taps that is measured with repeated 3D ultrasound (3D US) imaging of the lateral ventricles could be used to assess the risk of the future requirement of a VPS. METHODS: A total of 92 neonates with intraventricular hemorrhage who were treated in the NICU were recruited between April 2012 and November 2019. Only patients who required ventricular taps (VTs) were included in this study, resulting in the analysis of 19 patients with a total of 61 VTs. Among them, 14 patients were treated with a VPS, and in 5 patients the hydrocephalus resolved spontaneously. Parameters studied were total ventricular volume measured with 3D US, ventricular volume change after VT, the ratio between volume reduction and tap amount, the difference between tap amount and volume reduction after tap, the average tap amount, the average number of days between taps, pre-tap head circumference, and reduction in head circumference after tap. RESULTS: Statistically significant differences were found in ventricular volume reduction after tap (p = 0.007), the ratio between volume reduction and tap amount (p = 0.03), the difference between tap amount and volume reduction after tap (p = 0.05), and the interval of days between taps (p = 0.0115). CONCLUSIONS: Measuring with 3D US before and after VT can be a useful tool for quantifying ventricular volume. The findings in this study showed that neonates who experience a large reduction of ventricular volume after VT are more likely to be treated with a shunt than are neonates who experience a small reduction.

Is ventricular lavage a novel treatment of neonatal posthemorrhagic hydrocephalus? a meta analysis.

INTRODUCTION: Intraventricular hemorrhage (IVH) may produce obliterative arachnoiditis, which disrupts the flow and absorption of cerebrospinal fluid (CSF), resulting in posthemorrhagic hydrocephalus (PHH). PHH gives a high risk of neurofunctional impairment. Ventricular lavage is the treatment of choice for PHH in neonates with IVH for decades. It is developing with the combination of fibrinolytic therapy, also called drainage, irrigation, and fibrinolytic therapy (DRIFT), and with the use of neuroendoscopic apparatus, also called neuroendoscopic lavage (NEL). METHODS: This review is a meta-analysis using the PRISMA method guideline, including the clinical studies comparing ventricular lavage (VL) with standard treatment of PHH between 2000 and 2021. RESULTS: VL group reduced the shunt dependency compared to standard treatment (OR = 0.22; 95CI 0.05 to 0.97; p = 0.05). VL group has less infection risk compared to the standard treatment group (RR = 0.20; 95CI 0.07 to 0.59; p < 0.05). The severe neurofunctional outcome is similar between the two groups (OR = 0.99; 95CI 0.13 to 7.23; p = 0.99). The early approach treatment group may give better neurofunctional outcomes compared to the late approach (OR = 0.14; 95CI 0.06 to 0.35; p < 0.05). CONCLUSION: VL reduce the shunt dependency on the PHH, decreasing the shunt's related infection rate. The early ventricular lavage may give benefit for the neurocognitive outcome.

The induction of ferroptosis in posthemorrhagic hydrocephalus.

Posthemorrhagic hydrocephalus (PHH) is a common neurological disease characterized by the disordered secretion of cerebrospinal fluid from the choroid plexus, ventricular dilation, and increased intracranial pressure after hemorrhage. Although these pathological processes are well established, the effective biomarkers for the diagnosis of PHH are still limited, largely because the underlying mechanisms-including cell death in the choroid plexus-are not well defined. Ferroptosis, a newly recognized type of programmed cell death, has been found to play a key role in a variety of pathologic conditions and diseases, including Parkinson's and Alzheimer's diseases. However, whether ferroptosis is induced in PHH is still unknown. In the current study, a rat model of PHH was established to investigate the induction of ferroptosis in PHH. Along with defects in memory and cognition, we observed that rats with experimentally induced PHH also demonstrated lipid peroxidation (a key marker of ferroptosis), as well as a significant increase and a significant decrease in two ferroptosis-specific genes, ACSL4 and SLC7A11, respectively. Thus, ferroptosis may serve as an auxiliary indicator for the diagnosis of PHH.

Iron homeostasis and post-hemorrhagic hydrocephalus: a review.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Variability in the diagnostic and management practices of post-hemorrhagic ventricular dilatation in very preterm infants across Canadian centers and comparison with European practices.

OBJECTIVES: To investigate the variability in diagnostic and therapeutic approaches to posthemorrhagic ventricular dilatation (PHVD) among Canadian neonatal centers, and secondary exploration of differences in approaches between Canadian and European practices. METHODS: We conducted a survey among Canadian tertiary neonatal centers on their local practices for managing very preterm infants with PHVD. The survey covered questions on the diagnostic criteria, timing and type of interventions and resources utilization (transfer to neurosurgical sites and neurodevelopmental follow-up). In a secondary exploration, Canadian responses were compared with responses to the same survey from European centers. RESULTS: 23/30 Canadian centers (77%) completed the survey. There was no consensus among Canadian centers on the criteria used for diagnosing PHVD or to initiate intervention. The therapeutic interventions also vary, both for temporizing procedures or permanent shunting. Compared to European practices, the Canadian approach relied less on the sole use of ultrasound criteria for diagnosing PHVD (43 vs 94%, p < 0.0001) or timing intervention (26 vs 63%, p = 0.007). Majority of European centers intervened early in the development of PHVD based on ultrasound parameters, whereas Canadian centers intervened based on clinical hydrocephalus, with fewer centers performing serial lumbar punctures prior to neurosurgical procedures (40 vs 81%, p = 0.003). CONCLUSION: Considerable variability exists in diagnosis and management of PHVD in preterm infants among Canadian tertiary centers and between Canadian and European practices. Given the potential implications of the inter-center practice variability on the short- and long-term outcomes of preterm infants with PHVD, efforts towards evidence-based Canada-wide practice standardization are underway.

Imaging of Premature Infants.

According to the World Health Organization (WHO), 15 million babies are born preterm each year. Preterm infants are those born at less than 37 weeks, while extremely and very preterm neonates include those born at 22 to less than 32 weeks gestational age. Infants that fail to make it to term are missing a key part in neurodevelopment, as weeks 24 to 40 are a critical period of brain development. Neonatal brain injury is a crucial predictor for mortality and morbidity in premature and low birth weight (<1500 g) infants. Although the complications associated with preterm birth continue to be the number one cause of death in children under 5, the survival rates are increasing (Volpe, 2019). Despite this, the incidence of comorbidities, such as learning disabilities and visual and hearing problems, is still high. The functional deficits seen in these infants can be contributed to the white matter abnormalities (WMA) that have been found in 50% to 80% of extremely and very preterm neonates. While numerous, the etiology of the neonatal brain injury is essential for determining the mortality and morbidities of the infant, as there is an increased risk for both intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), which can be attributed to their lack of cerebrovascular autoregulation and hypoxic events. Neuroimaging plays a key role in detecting and assessing these neurologic injuries that preterm infants are at risk for. It is essential to diagnose these events early on to assess neurologic damage, minimize disease progression, and provide supportive care. Brain MRI and cranial ultrasound (CUS) are both extensively used neuroimaging techniques to assess WMA, and it has become ever more important to determine the best imaging techniques and modalities with the increasing survival rates and high incidence of comorbidities among these infants.

Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters.

INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis. METHODS: CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions. RESULTS: The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions. CONCLUSIONS: CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.

Elevated cerebrospinal fluid iron and ferritin associated with early severe ventriculomegaly in preterm posthemorrhagic hydrocephalus.

OBJECTIVE: Posthemorrhagic hydrocephalus (PHH) following preterm intraventricular hemorrhage (IVH) is among the most severe sequelae of extreme prematurity and a significant contributor to preterm morbidity and mortality. The authors have previously shown hemoglobin and ferritin to be elevated in the lumbar puncture cerebrospinal fluid (CSF) of neonates with PHH. Herein, they evaluated CSF from serial ventricular taps to determine whether neonates with PHH following severe initial ventriculomegaly had higher initial levels and prolonged clearance of CSF hemoglobin and hemoglobin degradation products compared to those in neonates with PHH following moderate initial ventriculomegaly. METHODS: In this observational cohort study, CSF samples were obtained from serial ventricular taps in premature neonates with severe IVH and subsequent PHH. CSF hemoglobin, ferritin, total iron, total bilirubin, and total protein were quantified using ELISA. Ventriculomegaly on cranial imaging was assessed using the frontal occipital horn ratio (FOHR) and was categorized as severe (FOHR > 0.6) or moderate (FOHR ≤ 0.6). RESULTS: Ventricular tap CSF hemoglobin (mean) and ferritin (initial and mean) were higher in neonates with severe versus moderate initial ventriculomegaly. CSF hemoglobin, ferritin, total iron, total bilirubin, and total protein decreased in a nonlinear fashion over the weeks following severe IVH. Significantly higher levels of CSF ferritin and total iron were observed in the early weeks following IVH in neonates with severe initial ventriculomegaly than in those with initial moderate ventriculomegaly. CONCLUSIONS: Among preterm neonates with PHH following severe IVH, elevated CSF hemoglobin, ferritin, and iron were associated with more severe early ventricular enlargement (FOHR > 0.6 vs ≤ 0.6 at first ventricular tap).

Neuroendoscopic lavage versus traditional surgical methods for the early management of posthemorrhagic hydrocephalus in neonates.

OBJECTIVE: Despite advances observed in neonatal neurosurgery, treatment of posthemorrhagic hydrocephalus (PHH) remains a major challenge. This study aims to observe the outcomes of the application of the neuroendoscopic method for treating early-stage posthemorrhagic hydrocephalus. METHODS: A total of 60 medical cases were studied retrospectively. From 2016-2021, the patients were treated at the neonatal intensive care unit (NICU). As an initial neurosurgical intervention, 19 neonates (A) underwent neuroendoscopic lavage (NEL) of the ventricular system and evacuation of posthemorrhagic debris via ventricular washout. A total of 36 neonates (B) were treated via traditional surgical methods, out of which 24 neonates underwent ventricular reservoir implantation (VAD) and 12 underwent ventriculostomy (EVD). Of the 60 patients, there were 5 neonates (C), who were treated directly by ventriculoperitoneal (VP) shunting after serial ventricular/lumbar punctures. As the inclusion and surgical criteria were significantly different for this group, their data were evaluated separately. Accordingly, these patients were divided into three (A, B, and C) groups. RESULTS: The gestational age of group A neonates (31 weeks) was slightly higher than the gestational age of group B (29.1 weeks). During their hospitalization, 15 neonates (78.94%) from group A and 26 (83.87%) neonates from group B required shunting. In group B, 5 patients (12.19%) died before the need for shunting occurred. No lethal outcomes were observed in group A, and 9 (25%) patients from group B died during hospitalization. In group A, central nervous system (CNS) infections developed in 3 patients, which is much less than the 18 patients in group B. NEL was found to give better neurological outcomes in patients with intraventricular hemorrhages. Serial ventricular/lumbar puncture can be used as a life-saving manipulation in very unstable patients to temporarily decreasing intracranial pressure. Its frequent use is associated with brain parenchymal damage and poor neurological outcome. CONCLUSION: The neuroendoscopic method of treating neonatal posthemorrhagic hydrocephalus is a safe and effective one. Its application reduces the period of patient hospital stay, the incidence of meningitis, and the frequency of development of multiloculated hydrocephalus.